USOO7687533B2

(12) United States Patent (10) Patent No.: US 7,687,533 B2 Critcher et al. (45) Date of Patent: Mar. 30, 2010

(54) N-(1-ARYLPYRAZOL-4L) SULFONAMIDES EP 546391 6, 1993 AND THEIR USE AS PARASITICDES EP 59.4291 4f1994 EP 626.375 11, 1994 (75) Inventors: Douglas James Critcher, Sandwich EP 1319657 6, 2003 (GB); Nigel Derek Arthur Walshe, WO WO87,03781 7, 1987 Sandwich (GB); Christelle Lauret, WO WO91f11172 8, 1991 Sandwich (GB) WO WO93, 19053 9, 1993 WO WO93,25543 12/1993 (73) Assignees: Pfizer Inc., New York, NY (US); Pfizer WO WO94/O2518 2, 1994 Products Inc., Groton, CT (US) WO WO94, 15944 T 1994 - WO WO94,21606 9, 1994 (*) Notice: Subject to any disclaimer, the term of this WO WO95/22552 8, 1995 patent is extended or adjusted under 35 WO WO96, 11945 4f1996 U.S.C. 154(b) by 607 days. WO WO96, 15121 5, 1996 WO WO98,24767 6, 1998 (21) Appl. No.: 10/593,133 WO WO98.28278 7, 1998 WO WO98,55148 12/1998 (22) PCT Filed: Mar. 7, 2005 WO WO98,57937 12/1998 (86). PCT No.: PCT/B2005/000597 W WS 1 3. S 371 (c)(1) WO WOO1, 19798 3, 2001 (2), (4) Date: Nov.30, 2006 WO WOO2/O58690 8, 2002 WO WOO3,O37274 5, 2003 (87) PCT Pub. No.: WO2005/090313 WO WOO3,051833 6, 2003 WO WO2004/OOO318 12/2003 PCT Pub. Date: Sep. 29, 2005 WO WO2004/043951 5, 2004 WO WO2004/043951 A1 * 5, 2004 (65) Prior Publication Data WO WO2004/049797 6, 2004 US 2008/O26 1940 A1 Oct. 23, 2008 Related U.S. Application Data OTHER PUBLICATIONS (60) Provisional application No. 60/.571,415, filed on May Vippagunta et al. (Advanced Drug Delivery Reviews, 48 (2001), pp. 13, 2004. 3-26).* (Continued) (30) Foreign Application Priority Data Primary Examiner Kamal A Saeed Mar. 18, 2004 (GB) ...... O4O6137.O Assistant Examiner Valerie Rodriguez-Garcia (74) Attorney, Agent, or Firm Thomas A. Wootton; Paul M. (51) Int. Cl. Misiak AOIN 43/56 (2006.01) (52) U.S. Cl...... 514/.407: 548/371.4 (57) ABSTRACT (58) Field of Classification Search ...... 514/.407; 548/371.4 See application file for complete search history. The invention relates to a sulfonamide compound of formula (I) or a pharmaceutically, veterinarily or agriculturally (56) References Cited acceptable salt or solvate thereof, where the groups R'-Rare described in the description, to compositions comprising U.S. PATENT DOCUMENTS Such compounds, processes for their synthesis and their use as 5,015,630 A 5, 1991 Fisher et al. parasiticides. 5,478,855 A 12/1995 Suzuki et al. 5,618,945 A 4/1997 Cazado et al. 6,106,864 A 8, 2000 Dolan et al. (I) 2002fOO16333 A1 2/2002 Faraci et al. * Rs FOREIGN PATENT DOCUMENTS R2 N-k DE 19511269 10, 1995 ( \ \, DE 1952O936 12/1996 N EP 192951 1, 1986 YN R5 EP 234119 12, 1986 EP 3O2328 2, 1989 k EP 357460 3, 1990 EP 382173 8, 1990 EP 444964 9, 1991 EP 503.538 9, 1992 8 Claims, No Drawings US 7.687,533 B2 Page 2

OTHER PUBLICATIONS Chemical abstracts service, Columbus, OH, USA Xp002330926, retrieved from STN accession No. 1964:3141 rn 947 11-31-6. Souillac, et al., Characterization of Delivery Systems, Differential Database crossfire beilstein institut Zur foerderung der chemischen Scanning Calorimetry, pp. 217-218 (in Encyclopedia of Controlled wissenschaften; Xp002330927 Beilstein registry No. 316683. Drug Delivery, 1999, John Wiley & Sons, pp. 212-227).* GuarneriMetal. “Contributo allaconoscenzadi pirazolsulfonamidi s Haleblian, Journal of Pharmaceutical Science, 64(8), pp. 1269-1288, Annali di Chimica, vol. 49, 1959, pp. 958-963. Aug. 1985. Koch Aetal. Quantitative Structure-Activity Relationships. vol. 12, Larsen. “Design and Application of prodrugs.” Textbook of Drug No. 4, 1993 pp. 373-382. Design and Discovery, 3rd Edition, 2002, pp. 410-458, Taylor and Alberti Cetal. Farmaco, Edizione Scientifica, vol. 21, No. 12, 1966, Francis Ltd., London. pp. 883-891. Liang and Chen, Expert Opinion in Therapeutic Patents, 11(6), pp. Alberti C et al. Farmaco, Edizione Scientifica, vol. 19, No. 7, 1964, 981-986, 2001. pp. 618-637. Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14, 2001. Alberti C et al. Farmaco, Edizione Scientifica, vol. 17, No. 6, 1962, Finnin and Mogan, Journal Pharm Sci. 88(10). 955-958, Oct. 1999. pp. 460-467. Wolniewicz & Dmowski, J. Fluorine Chem., 2001, 109, 2, 95 (wo Alberti C et al. Farmaco, Edizione Scientifica, vol. 29, No. 12, 1974 spec p. 124). pp. 957-966. Hainzl, D., et al. Chemical Research in Toxicology, 11(12), pp. Alberti C et al. Farmaco, Edizione Scientifica, vol. 26, No. 1, 1971, 1529-1535, 1998. pp. 66-88. Hall, H.K., et al. Journal of the American Chemical Society. 97(4), Fusco, R. et al. Farmaco, Edizione Scientifica, vol. 23, No. 19, 1968 pp. 800-807, 1975. pp. 919-944. Chemical Abstracts Service, Columbus OH, USA; xp002330925, retrieved from STN. Accession No. 1969:36415, m 23142-47-4. * cited by examiner US 7,687,533 B2 1. 2 N-(1-ARYLPYRAZOL-4L) SULFONAMIDES ing parasites and prevent infestation. This has benefits in AND THEIR USE AS PARASITICDES terms of compliance and labour costs as less frequent dosing is needed and the dosing timetable is easier. This in turn CROSS-REFERENCE TO RELATED assists in minimising the re-incidence of infestation as a Sub APPLICATIONS sequent dosage is less likely to be overlooked. It is an aim of the present invention to overcome various This application is the national phase of international disadvantages of or improve on the properties of prior art application PCT/IB2005/000597, filed on Mar. 7, 2005 which compounds. Thus it is an aim of the invention to provide an claims the benefit of Great Britain Application No. arylpyrazole which has improved activity relative to prior art 0406137.0, filed Mar. 18, 2004 and U.S. Provisional Appli 10 cation No. 60/571,415, filed May 13, 2004, hereby incorpo compounds against parasites. The compounds of the present rated by reference in its entirely. invention have especially good ability to control a broad The present invention relates to pesticidal compounds and spectrum of arthropods as shown by the results of tests dem a process for their preparation. More particularly, the present onstrating their potency and efficacy. Surprisingly, we have invention relates to N-(1-arylpyrazol-4-yl)sulfonamides 15 found that the compounds of the present invention are signifi which possess antiparasitic activity. In particular, we have cantly more active against fleas and/or have a greater duration identified a series of N-(1-arylpyrazol-4-yl)sulfonamides of action than similar prior art compounds. One advantage of which have improved activity and/or a longer duration of the compounds of the present invention is that treatment with action and/or improved safety. these compounds can also lead to a reduced incidence of Sulphamoyl (reversed Sulphonamides) arylpyrazoles for allergy to the parasite which is responsible for the infestation. the control of arthropod, plant nematode, or helminth pests For example, the incidence of flea allergies which can cause have also been disclosed in, for example, EP-234119, flea allergic dermatitis may be reduced. US-2002016333, WO-0258690 and DE-19511269. It is also desirable that the compounds of the present inven 5-Sulphonamido-1-arylpyrazoles have been disclosed as tion should have an improved pharmacokinetic profile, having utility as herbicides in, for example, EP-0192951 and 25 improved safety, longer half-life, improved persistence and EP-3O2328. improved solubility. It is also desired that the compounds U.S. Pat. No. 5,618.945 relates to a process for sulphiny should lead to a reduced incidence of emesis. lation of compounds such as arylpyrazoles, by the treatment Unfortunately, many potent pesticidal aryl pyrazoles and of a compound such as RS(O)X, where X is commonly Cl, their derivatives also have undesirable effects such as emesis and discloses compounds of formula R—S(O)NH-Het where 30 Het can be N-arylpyrazole, although it is not clear which on animals regardless of whether or not the animal itself is substitution pattern is referred to. being treated directly. This unwanted toxicity can limit the Some pyrazoles possessing bactericidal activity are dis dose that can be used and thus limits the range of parasites that closed in WO-9315060 for use in crop protection. Among the can be controlled. Thus it is an aim of the present invention to many structures disclosed are some N-heterocyclic pyrazol 35 address the need for the development and use of new and 4-yl Sulfonamides. efficacious pesticides that can control pests for longer periods WO00/71532, WO03/51833, WO01/19788, WO01/ of time but which are not toxic to animals susceptible to pest 19798, WO03/37274, WOO4/00318, WO98/57937 and infestations or animals that might come into contact with WO96/12706 all generally describe pyrazole compounds for areas Susceptible to pest infestations. uses unrelated to those described for the present invention. 40 It is a further aim to provide a convenient, synthetically The prior art compounds do not always demonstrate good efficient process for the production of the aryl pyrazoles and activity or a long duration of action against parasites. Simi the intermediates of the present invention. It is also an aim to larly, some parasiticidal agents are useful only for a narrow provide a route to the compounds of the invention which spectrum of parasites. Modern pesticides must meet many offers a good yield and which ideally avoids the use of unnec demands, including long duration, broad spectrum of action, 45 essary synthetic steps and/or purification steps. low toxicity, combination with other active substances and/or The present invention satisfies some or all of the above different formulation excipients. The occurrence of resis aims. tance is also possible. Consequently the search for new anti According to the present invention, there is provided a parasitic agents is ongoing and there is a constant demand for compound of formula (I) or a pharmaceutically, veterinarily novel compounds which are advantageous over the known 50 or agriculturally acceptable salt or Solvate thereof, compounds in one or more of these aspects. The aim of the present invention is to provide a compound which can be conveniently administered as an antiparasitic (I) agent. In particular an agent is sought which can be used in the treatment of human or animal parasitic diseases or can be 55 * Rs used in agricultural or horticultural applications. One aim is R2 N-k to provide an agent which can be used in humans, livestock | \ \, (including sheep, pigs and cattle), companion animals (in N cluding cats, dogs and horses). The agent is intended to con N R5 trol arthropods, arachnids, nematodes and helminths includ 60 ing flies, fleas, mites and ticks. k Another aim is to provide compounds with good pharma cokinetics and extended duration of action and thus which prevents re-establishment of infestation over long periods of wherein: time. 65 R" represents phenyl or heteroaryl, optionally substituted by It is a further aim to provide a compound suitable for oral, one or more groups independently selected from halo, parenteral or topical administration which is able to kill exist cyano, hydroxy, C. alkyl, Ce haloalkyl, C- alkoxy, US 7,687,533 B2 3 4 C- haloalkoxy, Co alkanoyl, C- haloalkanoyl, where heteroaryl represents a 5 or 6 membered aromatic ring —S(O), Calkyl, -S(O)Chaloalkyl and pentafluo which contains 1-3 heteroatoms selected from N, O and S rothio; or 4-N atoms to form a tetrazolyl: R represents hydrogen, halo, cyano, nitro, C. alkyl, C where both phenyl and het may be optionally substituted, haloalkyl, C2-alkenyl, Chaloalkenyl, C2-alkynyl, C2 where the valence allows, by one or more substituents haloalkynyl. —S(O)C alkyl, - S(O), Chaloalkyl, independently selected from halo, hydroxy, cyano, nitro, —(Co-alkylene)-Cs cycloalkyl, C. alkanoyl, option C. alkyl, Chaloalkyl, Ce alkenyl, Chaloalkenyl, ally substituted by C. alkoxy, Chaloalkanoyl, option Coalkoxy, Chaloalkoxy, C-8 cycloalkyl, C ally substituted by C. alkoxy, phenyl, het, —(Co-alky alkanoyl, Chaloalkanoyl, C. alkylcarbonyloxy, C. lene)-N(R)R’, —(Coalkylene)-C(O)NR'R'' O 10 alkoxycarbonyl and NR'R'': —(Co-alkylene)-N(R)C(O)R: where C-scycloalkyl may be optionally Substituted by one or R represents C- alkyl, C. haloalkyl, C. alkenyl, C more groups independently selected from halo, Calkyl, haloalkenyl, —(Co-alkylene)-Cas cycloalkyl, Chaloalkyl, C. alkenyl, Chaloalkenyl, hydroxy, —(Calkylene)-S(O)Calkyl, —(Calkylene)- Calkoxy and Chaloalkoxy; and S(O)Chaloalkyl, —(Co-alkylene)-N(R)R’ 15 where any alkylene or alkenylene group may be optionally —(Co-alkylene)-phenyl, —(Co-alkylene)-het, substituted by one or more halo. —(Calkenylene)-phenyl, —(Calkenylene)-het, C According to formula (I), Chaloalky, Chaloalkoxy or alkanoyl, Chaloalkanoyl or N(R)CO.R. Chaloalkanoyl means a C- alkyl, C- alkoxy or C-gal R" represents hydrogen, C. alkyl, Chaloalkyl, kanoyl Substituted by 1 to 5 halo groups chosen indepen —(Co-alkylene)-R or -(C-3alkylene)-R: dently, Suitably fluoro groups. Also, halo means a group or R and R taken together with the nitrogen and sulphur selected from fluoro, bromo, chloro, bromo or iodo. atoms to which they are attached form a 4 to 7-membered According to formula (I), a C- alkyl, Ce alkoxy or ring, Calkanoyl, including the corresponding halo Substituted R represents hydrogen, hydroxy, halo, C. alkyl, C groups, may be straight-chained or, where possible, haloalkyl, C2-alkenyl, C2-shaloalkenyl, Coalkoxy, C. 25 branched. An alkylene group refers to a straight-chained or, haloalkoxy, N=C(R')(Coalkylene)-R'' or - N(R') where possible, branched linking group and alkenylene refers R13; to a linking group containing one double bond. For the avoid R represents C, alkyl or Chaloalkyl; ance of any doubt, a Coalkylene group refers to a direct link R" represents C-scycloalkyl, -S(O),R, phenyl, het, between the connecting groups. COR or C(O)N(R)R’; 30 Suitably, R is substituted phenyl, substituted in one or R represents hydroxy, C, alkoxy, Chaloalkoxy, cyano, both of the 2- and 6-positions and at the 4-position with a N(R')R’ or O C(O)R; substituent independently selected from the group compris R represents C, alkyl, Ce haloalkyl, Cscycloalkyl, ing halogen, e.g. chloro, Ce alkyl, e.g. methyl, C. - N(R)R’, phenyl or het: haloalkyl, e.g. trifluoromethyl, Ce alkoxy, e.g. methoxy, R" represents hydrogen, Ce alkyl or Chaloalkyl; 35 C. alkylthio, e.g. methylthio. Chaloalkoxy, e.g. trifluo R'' represents hydrogen, hydroxy, Calkoxy, N(R)R’, romethoxy or difluoromethoxy, Ce haloalkylthio, e.g. trif phenyl, het or Cscycloalkyl, with the proviso that luoromethylthio, and pentafluorothio. -N=C(R')(Coalkylene)-R'' is not-N=CH: Preferably, R' is phenyl substituted at one or both of the 2 R" represents hydrogen, C. alkyl, Chaloalkyl, Calk and 6-positions by halo, e.g. chloro, and at the 4-position by enyl or Chaloalkenyl: 40 a group selected from Calkyl substituted with one or more R" represents hydrogen, C. alkyl, Chaloalkyl, Calk independently selected halo groups, e.g. trifluoromethyl, Ca enyl, C. haloalkenyl C-cycloalkyl, phenyl, het, alkoxy substituted with one or more independently selected —(Calkylene)-R'', C(O).R' or CONCR) halo atoms, e.g. trifluoromethoxy or difluoromethoxy, C. (Calkylene)-R'': alkylthio Substituted with one or more independently selected R" represents hydroxy, Cisalkoxy, C-shaloalkoxy, Cascy 45 halo atoms, e.g. trifluoromethylthio, and pentafluorothio. cloalkyl, phenyl, het or N(R)R’; More preferably, R' is a phenyl group which bears chloro R" represents C, alkyl, Chaloalkylor—(Coalkylene)- Substituents at the 2- and 6-positions, and a Substitutent at the Calkoxy. 4-position selected from trifluoromethyl, difluoromethoxy, R" represents hydrogen, Ce alkyl or Chaloalkyl; trifluoromethoxy, trifluoromethylthio and pentafluorothio. R7 represents hydrogen or N(R)R’; 50 Still more preferably, R is a phenyl group in which the 2 RandR independently represent hydrogen, C-alkyl, C and 6-substituents are chloro and the 4-substituent is selected haloalkyl, Calkenyl or Chaloalkenyl, or R' addition from trifluoromethyl and pentafluorothio. ally represents —(Co-alkylene)-Cs cycloalkyl, Where R' is a heteroaryl, R' is suitably a 3,5-disubstituted —(Co-alkylene)-phenyl or —(Co-alkylene)-het, or pyridin-2-yl, wherein the 3-substituent is selected from together Rand R' form a 4- to 7-membered ring, option 55 hydrogen and halo, and the 5-substituent is selected from ally Substituted by one or more groups independently halo, e.g. chloro, pentafluorothio. S(O)C alkyl, S(O)Cl. Selected from halo, hydroxy, Calkyl, Chaloalkyl, C. haloalkyl, Calkyl, Chaloalkyl, e.g. trifluoromethyl, C. alkoxy and Chaloalkoxy; alkoxy and Chaloalkoxy. R represents hydrogen, C alkyl, Chaloalkyl, C2-alk Suitably, het represents an optionally Substituted aromatic enyl, Ce haloalkenyl, —(Co-alkylene)-Cs cycloalkyl, 60 or non-aromatic 5- or 6-membered heterocyclic group con —(Co-alkylene)-phenyl or —(Co-alkylene)-het: taining 1, 2 or 3 heteroatoms, which are independently in represents an integer selected from 0, 1 and 2; selected from N, O or Satoms. More suitably, het is selected p represents an integer selected from 1 and 2: from pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, where het represents a four- to seven-membered heterocyclic isothiazolyl, furanyl, thiophenyl, pyrrolyl, triazolyl, oxadia group, which is aromatic or non-aromatic and which con 65 Zolyl azetidinyl, pyrrolidyl, piperidyl, pyridyl, pyrazinyl, tains one or more heteroatoms selected from nitrogen, oxy pyrimidyl and morpholinyl, wherein the aforementioned gen, Sulfur and mixtures thereof. groups may be optionally Substituted by one or more groups US 7,687,533 B2 5 6 independently selected from C alkyl, e.g. methyl, C. pyrazinyl, pyrimidyl and morpholinyl, wherein the afore haloalkyl, e.g. trifluoromethyl, halogen, e.g. fluoro, and mentioned groups may be optionally substituted by one or N(R)R’, e.g. amino. more groups independently selected from Calkyl, halogen, Suitably, R is selected from hydrogen, cyano, C. e.g. fluoro, and N(R)R, e.g. amino. More preferably, when haloalkyl, e.g. trifluoromethyl, Css cycloalkyl, e.g. cyclopro R" represents —(Cosalkylene)-het, Co-salkylene is a meth pyl, C-calkanoyl, e.g. acetyl, and —C(O)N(R)R’, e.g. ami ylene link and het is selected from imidazolyl, isoxazolyl, nocarbonyl. oxadiazolyl and pyridyl, where each ring may be optionally More preferably, R is selected from hydrogen, trifluorom Substituted by C. alkyl, e.g. methyl. ethyl, cyclopropyl, acetyl, aminocarbonyl and cyano. Yet When R represents —(Coalkylene)-phenyl, phenyl is more preferably, R is selected from trifluoromethyl and 10 Suitably optionally Substituted by one or more halo, e.g. cyano. Most preferably, R is cyano. fluoro, e.g. 4-fluoro. When R is —(Coalkylene)-N(R)R’, suitably the N is When R represents —(C-alkylene)-N(R)R’, this is directly linked and N(R)R’ is suitably amino ordi-C alky suitably 2-N,N-dimethylaminoethyl. lamino, e.g. N,N-dimethylamino. When R represents —(Calkylene)-C(O)N(R)R, this Suitably, R is selected from C, alkyl, e.g. methyl, ethyl, 15 is suitably aminocarbonylmethyl. n-propyl or i-propyl, Chaloalkyl, e.g. trifluoromethyl or Suitably, R is selected from hydrogen, Ce alkyl, e.g. 2.2.2-trifluoroethyl, C-scycloalkyl, e.g. cyclopropyl. methyl, ethyl or isopropyl, Ce haloalkyl, e.g. trifluorom —(Calkylene)-S(O), Calkyl, e.g. methylsulfonylmethyl ethyl, 2.2.2-trifluoroethyl, 2,2-difluoroethyl 2-fluoroethyl or or 1-methylsulfonylethyl, N(R)R’, e.g. amino or N,N-dim 2.2.3,3,3-pentafluoropropyl. —(Co-alkylene)-Cas ethylamino, N(R)CO.R, e.g. tert-butoxycarbonylamino, cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclo optionally substituted phenyl, e.g. by one or more halo, e.g. propylmethyl, (1-methylcyclopropyl)methyl, 2.2-difluoro fluoro, optionally Substituted benzyl, e.g. by one or more cyclopropyl or 1-(trifluoromethyl)cyclopropylmethyl, cya halo, e.g. fluoro. —(Calkenylene)-phenyl, e.g. 2-phe nomethyl, 2-hydroxyethyl, —(Calkylene)-het, e.g. nylethenyl, and Calkanoyl, e.g. propan-2-oyl. pyrazol-3-ylmethyl, pyrimidin-4-ylmethyl, pyridin-3-ylm Preferably, R is selected from C, alkyl, e.g. methyl, 25 ethyl 2-pyrrolidin-1-ylethyl, 2-morpholin-4-ylethyl, 1-me ethyl, n-propyl or i-propyl, Ce haloalkyl, e.g. trifluorom thyl-1H-imidazol-2-ylmethyl, pyridin-4-ylmethyl, triazolyl ethyl or 2.2.2-trifluoroethyl, Cs cycloalkyl, e.g. cyclopro ethyl, 1,2,4-oxadiazol-3-ylmethyl, pyridin-2-ylmethyl or pyl. —(Calkylene)-S(O)Calkyl, e.g. methylsulfonylm (5-methylisoxazoly-3-yl)methyl, -(Co-alkylene)-phenyl, ethyl, N(R)R, e.g. amino or N,N-dimethylamino, Ca e.g. benzylor 4-fluorobenzyl, -(Co-alkylene)-S(O),R, e.g. alkanoyl, e.g. propan-2-oyl, - N(R)CO.R. e.g. tert-bu 30 1,1,1-trifluoromethylsulfonyl, aminosulfonyl, N,N-dimethy toxycarbonylamino, phenyl, optionally Substituted by one or laminosulfonyl, cyclopropylsulfonyl, methylsulfonyl, more halo, e.g. 3,4-difluorophenyl, and benzyl. 4-fluorophenylsulfonyl, 2,4-difluorophenylsulfonyl, (meth More preferably, R is selected from methyl, ethyl, trifluo ylsulfonyl)methyl O 2.2.2-trifluoroethylsulfonyl, romethyl and 2.2.2-trifluoroethyl. Most preferably, R is —(C-alkylene)-O C(O)R, e.g. tert-butylcarbonyloxym methyl. 35 ethyl, —(Calkylene)-C(O)N(R)R, e.g. aminocarbonyl Where R is —(Co-alkylene)-R", the link is suitably a methyl, and —CO.R. e.g. methoxycarbonyl. direct or a methylene link. More preferably, R is selected from hydrogen, methyl, Where R is —(Co-alkylene)-R, the link is suitably a ethyl, trifluoromethyl, 2,2-difluoroethyl, 2.2.2-trifluoroethyl, methylene or ethylene link. methylsulfonyl, trifluoromethylsulfonyl, 2.2.2-trifluoroeth Where R represents —(Coalkylene)-S(O).R., n is suit 40 ylsulfonyl, aminosulfonyl, N,N-dimethylaminosulfonyl, ably 0 or 2, preferably 2, and R is suitably selected from C. methylsulfonymethyl, cyclopropyl, cyclobutyl, cyclopropyl alkyl, e.g. methyl, Chaloalkyl, e.g. trifluoromethyl or 2.2, methyl, 1-(trifluoromethyl)cyclopropylmethyl, cyanom 2-trifluoroethyl, Css cycloalkyl, e.g. cyclopropyl, N(R)R’, ethyl, methoxycarbonyl, triazolylethyl, pyrimidin-4-ylm e.g. amino or N,N-dimethylamino, and phenyl, optionally ethyl, 1,2,4-oxadiazol-3-ylmethyl, pyrazol-3-ylmethyl, substituted by one or more halo, e.g. fluoro. Preferably, n is 2, 45 1-methyl-1H-imidazol-2-yl, 5-methyl-isoaxazol-3-ylm Co-alkylene is a direct link and R represents C-calkyl, e.g. ethyl 2-pyridin-4-ylethyl, aminocarbonylmethyl, benzyl and methyl, or Chaloalkyl, e.g. trifluoromethyl or 2.2.2-trif 4-fluorobenzyl. luoroethyl. Where R and R' form a 4 to 7 membered ring, this is Where R' represents —(Co-alkylene)-Css cycloalkyl, Suitably a dioxidoisothiazolidinyl group, e.g. 1,1-dioxido Co-alkylene is suitably a direct link or methylene, Cls 50 isothiazolidin-2-yl, or a dioxido-thiazinanyl group, e.g. 1.1- cycloalkyl Suitably represents cyclopropyl, cyclobutyl or dioxido-1,2-thiazinan-2-yl group. cyclopentyl, optionally Substituted by one or more halo, e.g. Where R is N=C(R')(Coalkylene)-R'', R' is suit fluoro, Ce alkyl, e.g. methyl or Chaloalkyl, e.g. trifluo ably hydrogen and the Co-salkylene is suitably a direct link. romethyl. Where R represents —(Co-alkylene)-Cls R' is suitably Calkoxy, e.g. ethoxy, N(R)R’, e.g. N.N- cycloalkyl, a preferred group is 1-(trifluoromethyl)cyclopro 55 dimethyl, or phenyl, optionally substituted by one or more pylmethyl. hydroxy. When R represents —(Coalkylene)-het, the link is suit R" is suitably hydrogen or methyl, preferably hydrogen. ably a methylene or ethylene link and het is suitably selected Where R' represents —(Calkylene)-R, the C-alky from pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, lene is Suitably a methylene, ethylene or propylene link and isothiazolyl, furanyl, thiophenyl, pyrrolyl, triazolyl, oxadia 60 R'' is suitably Calkoxy, e.g. ethoxy, phenyl, N(R)R’, Zolyl pyrrolidyl, pyridyl, pyrazinyl, pyrimidyland morpholi e.g. N,N-dimethylamino, het, e.g. pyrrolidinyl, morpholinyl, nyl, wherein the aforementioned groups may be optionally aZetidinyl, piperidinyl or pyridyl, or Cscycloalkyl, e.g. Substituted by one or more groups independently selected cyclopropyl. from C alkyl, e.g. methyl, halogen, e.g. fluoro, and N(R) Where R' represents C(O).R.' and prepresents 1, R' is R", e.g. amino. Preferably, when R represents —(C-alky 65 suitably C-alkyl, e.g. methyl. When p represents 2, R' is lene)-het, het is selected from pyrazolyl, imidazolyl, isox Suitably Calkyl, e.g. methyl, or Chaloalkyl, e.g. 2.2.2- azolyl, pyrrolyl, triazolyl, oxadiazolyl pyrrolidyl, pyridyl, trifluoroethyl. US 7,687,533 B2 7 8 Where R' represents –C(O)N(R')(Calkylene)-R'7, R" is selected from: hydrogen; C. alkyl, -(CH2), Css R" is suitably hydrogen and Calkylene is suitably ethyl cycloalkyl which may be optionally substituted with one or ene. R'' is suitably amino. more substituents independently selected from: halo and R" is suitably selected from hydrogen, methyl, benzyl, Co alkyl, -(CH2), S(O).R"; —CO(C- alkyl); cyclopropylmethyl, 2-N,N-dimethylaminoethyl, acetyl, -(CH), het; and –C(O)NR'R'': methoxymethylcarbonyl, methoxycarbonyl, 2.2.2-trifluoro or R." and R' taken together with the nitrogen and sulphur ethoxycarbonyl, N-pyrrolidinylethyl, N-morpholinylethyl, atoms to which they are attached form a 4 to 7-membered N-piperidinylethyl, pyridin-4-ylmethyl, N-azetidinylethyl r1ng, and aminoethylaminocarbonyl. R' is preferably hydrogen R" is selected from: hydrogen; hydroxy: C. alkyl; and R'' and R' are preferably both hydrogen. 10 NR'R'': halo and Calkoxy; Suitably, R is selected from hydrogen, halo, e.g. chloro, R" is selected from: C, alkyl; NR'R'', C.s cycloalkyl C. alkoxy, e.g. methoxy, N=C(H)R'', where R'' is which may be optionally substituted with one or more ethoxy, N,N-dimethyl or phenyl, optionally substituted by Substituents independently selected from: halo and C. one or more hydroxy, e.g. 2,4-di-hydroxy, and —NR'R''. alkyl; het; and phenyl: e.g. amino, benzylamino, pyridin-4-ylmethylamino, 15 each na is independently 0, 1 or 2; 2-ethoxyethylamino, methylamino, methoxymethylcarbony each ma is independently 0, 1, 2 or 3: lamino, cyclopropylmethylamino, methylcarbonylamino, pa is 1 or 2; 2-N,N-dimethylaminoethyl(methyl)amino, 2-N-azetidinyl and wherein ethylamino, 2-N-pyrrolidinylethylamino, 2-N-morpholino het represents a four- to seven-membered heterocyclic group, ethylamino, 2-N-piperidinylethylamino, cyclopropylmethy which is aromatic or non-aromatic and which contains one lamino, methoxycarbonylamino, 2.2.2- or more heteroatoms selected from nitrogen, oxygen, Sul trifluoroethoxycarbonylamino and fur and mixtures thereof, and wherein said heterocyclic 2-aminoethylaminocarbonylamino. ring is optionally substituted and/or terminated where the Preferably, R is selected from hydrogen, amino, meth valence allows with one or more substituents selected oxymethylcarbonylamino, cyclopropylmethylamino, 3-N,N- 25 from: halo, cyano, nitro, Ce alkyl, Chaloalkyl, C. dimethylaminopropylamino, 2-N-azetidinylethylamino, alkoxy, OC(O)C alkyl, C(O)C alkyl, C(O)OC 2-N-piperidinylethylamino, 2-N-pyrrolidinylethylamino, alkyl, and NR'R'': 2-N-morpholinoethylamino, methoxycarbonylamino, each C alkyl group can independently be branched or ethoxyimino, phenylimino and 2,4-dihydroxyphenylimino. unbranched and optionally substituted by one or more Most preferably, R is amino. 30 groups selected independently from: cyano; halo: hydroxy: A Suitable Sub-group of the present invention is repre nitro; Coalkoxy: NR'R'': S(O)Cl. alkyl: S(O)Cls sented by compounds of formula (Ia), cycloalkyl: S(O)C alkylhet: Cs cycloalkyl, and phe nyl: 35 each phenyl may be optionally substituted by one or more 4 O (Ia) R 3. Substituents independently selected from: cyano; halo: V 1. R3a hydroxy; nitro, Calkyl, Chaloalkyl, and Calkoxy; and each R" and R” are independently selected from R2a N-SV hydrogen; C. alkyl, and Css cycloalkyl which may be optionally substituted with one or more substituents inde N) 40 pendently selected from: halo and C alkyl; or R“ and YN R5a R" may be taken together with the nitrogenatom to which k they are attached to form a 4 to 7-membered ring. A suitable group of compounds of formula (I) of the 45 present invention are those wherein: wherein N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluorothiophe R" is arylor heteroaryl optionally substituted by one or more nyl)-1H-pyrazol-4-yl)-N-(2,2-difluoroethyl)methane groups independently selected from: hydrogen; halo: C Sulfonamide; alkyl, C. alkoxy which may be optionally substituted N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluorothiophe with one or more independently selected halo atoms; 50 nyl)-1H-pyrazol-4-yl)-1,1,1-trifluoro-N-methylmethane —S(O)C alkyl; and pentafluorothio; cyano: C Sulfonamide; alkanoyl which may be optionally substituted with one or N-5-amino-3-cyano-1-2,6-dichloro-4-(trifluoromethyl) more independently selected halo atoms; phenyl)-1H-pyrazol-4-yl)-3,4-difluorobenzenesulfona R’ is selected from: hydrogen; halo: C. alkyl; mide; —S(O)C alkyl, -(CH2)Cs cycloalkyl which may 55 N-5-amino-3-cyano-1-2,6-dichloro-4-(trifluoromethyl) be optionally substituted with one or more substituents phenyl)-1H-pyrazol-4-yl)cyclopropanesulfonamide: independently selected from: halo and C alkyl, cyano; N-5-amino-3-cyano-1-2,6-dichloro-4-(trifluoromethyl) nitro; —(CH)NR'R'"; C, alkanoyl which may be phenyl)-1H-pyrazol-4-yl)-N-(cyclopropylmethyl)meth optionally Substituted by one or more groups indepen anesulfonamide; dently selected from halo and Calkoxy, phenyl, oxadia 60 N-5-amino-3-cyano-1-2,6-dichloro-4-(trifluoromethyl) zole; C(O)NR'R'': NRC(O)R’: Calkenyl; and phenyl)-1H-pyrazol-4-yl)-N-(cyanomethyl)methane C2-alkynyl, Sulfonamide; R" is selected from: C, alkyl, -(CH)NR'R'': N-5-amino-3-cyano-1-2,6-dichloro-4-(trifluoromethyl) —(CH2)Cs cycloalkyl which may be optionally Sub phenyl)-1H-pyrazol-4-yl)-N-(pyridin-2-ylmethyl)meth stituted with one or more substituents independently 65 anesulfonamide; Selected from: halo and C alkyl, -(CH2) phenyl: N-5-amino-3-cyano-1-2,6-dichloro-4-(trifluoromethyl) —CH=CH-phenyl; and —(CH), het; phenyl)-1H-pyrazol-4-yl)-N-benzylmethanesulfonamide:

US 7,687,533 B2 15 16 according to standard procedures during the synthesis of then Subsequently adding a mild base, typically potassium compounds of formula (I). In the processes described below, carbonate in a suitable solvent, such as N,N-dimethylforma for all synthetic precursors used in the synthesis of com mide and heating at elevated temperatures for several hours. pounds of formula (I), the definitions of R', R. R. R', and A compound of formula (I) where R is SO.R and Rand R, wherein R', R. R. R. and Rare as defined for formula Rare taken together with the nitrogen and Sulphur atoms to (I), are intended to optionally include suitably protected vari which they are attached to form a 4 to 7-membered bis ants, P', P, P, P and P. Such suitable protecting groups for Sulfonamide ring, may be prepared from a compound of these functionalities are described in the references listed formula (II) by the two step addition of a C- alkyl bis below and the use of these protecting groups where needed is sulfonyl chloride to a solution of a compound of formula (II) specifically intended to fall within the scope of the processes 10 in a suitable solvent, such as pyridine, and heating at reflux for described in the present invention for producing compounds several hours, typically overnight. of formula (I) and its precursors. When suitable protecting Compounds of formula (I) where R is an alkyl group may groups are used, then these will need to be removed to yield be prepared, for example, by reaction of the compound of compounds of formula (I). Deprotection can be effected formula (I) with a suitable alkylating agent, e.g. R. X. according to standard procedures including those described 15 where X may be any leaving group, typically 1, Br, Cl, OTs, in the references listed below. OTf, O-mesylate, or O-trichloromethylsulphonate, in a suit For example, when R in formula (I) is an unsubstituted able solvent, e.g. acetone, dichloromethane, acetonitrile, amino group, certain precursors may require protection of the dimethylformamide or N-methylpyrrolidinone, in the pres amino group in order to perform the necessary transforma ence of base, e.g. potassium carbonate, caesium carbonate, tions, for example, by an imidoformamide group Such as a and sodium hydride. Other salts may aid the reaction, for compound of formula (Ib), where R'-R are as described for example, Sodium iodide or potassium iodide. formula (I) and R represents - N=C(H) NR'R'', where A compound of formula (I) in which R is an alkyl group, R" and R' independently represent Calkyl, e.g. to form a may be prepared by alkylation of a compound of formula (I) N,N-dimethyl group. Such imidoformamides may be pre where R is hydrogen, using suitably acidic alcohol reagents pared by methods herein described and may be removed 25 via a Mitsunobu reaction. under Suitable acid conditions, such as at elevated with a A compound of formula (I) in which R is Calkoxycar Suitable acid Such as hydrochloric acid or para-toluene bonyl may be prepared by acylation of a compound of for Sulfonic acid in a solvent such as methanol or dioxane. mula (I), where R is H, with an alkylhaloformate, e.g. a According to a first general method, a compound of for chloroformate, in a suitable solvent, such as acetone at reflux mula (I), in which R is H and R', R, R and Rare as 30 temperature for several hours using a Suitable base such as previously defined for formula (I), may be prepared from a potassium carbonate. compound of formula (II): Standard chemical procedures may be used to modify sidechains R. R. R. and R of compounds of formula (I) (II) 35 provided that any reactive functional groups in the remaining NH2 sidechains are appropriately protected, as hereinbefore men tioned. For example, a compound of formula (I) in which R is CN may be converted to a compound of formula (I) where R is N R5 40 —C(O)N(R)R’ and C, alkanoylunderstandard conditions well-known to those skilled in the art. Compounds of formula (I) where R is —(Co-alkylene)- cyclopropyl may be prepared from compounds of formula (I) wherein R, R and Rare as previously defined for formula where R is the corresponding alkenyl by standard cyclopro (I) by Sulfonation by a Suitable Sulfonating agent, e.g. 45 panation procedures, e.g. conversion of an ethenyl derivative RSOC1 or a sulfonic acid anhydride under standard condi to the corresponding difluorocyclopropyl derivative by heat tions, e.g. in a Suitable solvent, for example, dichlo ing a solutionina Suitable solvent Such as toluene with methyl romethane, in the presence of base, typically pyridine/4-dim benzoate at elevated temperature followed by addition of ethylaminopyridine mixtures, under an inert atmosphere. trimethylsilyl-2,2-difluoro-2-(fluorosulfonyl)acetate drop Compounds of formula (I) where R is not hydrogen may 50 wise over several hours. Such transformations are also be prepared from compounds of formula (I) where R is described in WO98/24767. hydrogen by Standard procedures. For example, a compound Compounds of formula (I), where Risan Coalkenyl may of formula (I) where R is RSO may be prepared by the be prepared from the corresponding bromoalkyl compound addition of a suitable sulfonating agent, e.g. RSOCl, to a by dehydrobromination under standard conditions. Also, Solution of a compound of formula (I) in an aprotic solvent, 55 compounds of formula (I), where R is a bromoalkyl group e.g. acetonitrile or dichloromethane, in the presence of base, can also be used to prepare other compounds of formula (I) e.g., triethylamine, potassium carbonate or pyridine/4-dim where the bromo-group is displaced with a suitable nucleo ethylaminopyridine mixtures. Compounds of formula (II) phile e.g. a heteroaryl, in a Suitable polar solvent, in the may be bis-Sulfonated in a one pot process, underwell-known presence of a Suitable base. conditions, to form compounds of formula (I). 60 Compounds of formula (I) where R is a readily oxidisable A compound of formula (I) where R and R are taken group, can be used to prepare alternative compounds of for together with the nitrogen and Sulphur atoms to which they mula (I), e.g. conversion of thioethers and hydroxyl Substi are attached to form a 4 to 7-membered monosulfonamide tuted alkyl substituents to sulphones and carbonyl derivatives ring, may be prepared from a compound of formula (II), by respectively, using standard oxidising agents, such as Oxone the single step addition of a chloro-Calkylsulfonyl chloride 65 or those described in “Handbook of Reagents for Organic to a solution of a compound of formula (II) in a suitable Synthesis—Oxidising and Reducing Agents' edited by S. D. Solvent, such as pyridine, allowing the reaction to progress Burke and R. L. Danheiser. US 7,687,533 B2 17 18 Compounds of formula (I) where R is an alkyl group hours, to give the nucleophilically substituted product e.g. a containing an aldehyde or ketone group can be prepared by secondary or tertiary amine substituted derivative. oxidation of the corresponding hydroxyalkyl group under A compound of formula (II) may be prepared as shown in standard conditions, such as Dess-Martin periodinane in an aprotic solvent, such as dichloromethane. The resulting alde Scheme 1 below, wherein R', R and R are as previously hyde or ketone groups can be further treated with nucleophilic defined, the CO Me group is illustrative of any carboxylic reagents, in a Suitable solvent, typically tetrahydrofuran, and acid ester group and the -CO(CH2)2SiOCH) is illustrative optionally in the presence of a suitable catalyst, to give the of any suitable amino protecting group resulting from the nucleophilically substituted secondary or tertiary alcohol. Curtius rearrangement. Additionally, compounds of formula (I) in which R is 10 —(Calkylene)-COH may be prepared by Saponification of the corresponding carboxylic acid ester. Scheme 1 A compound of formula (I) in which R is NH, may be R2 H R2 halo R2 COOCH used to prepare an alternative compound of formula (I) by derivatisation of the amino group, including methods as dis 15 cussed above for formation of R groups, e.g. alkylation or YN R5 co- YN R5 co- YN R5 acylation. Additionally, a compound of formula (I) where R R1 R1 R1 represents an optionally Substituted C. alkylimino group, (III) (IV) (V) may be prepared by heating the corresponding compound of formula (I) where R represents NH, with an akdehyde, at elevated temperature, with a suitable catalyst, typically p-toluenesulfonic acid, with the optional addition of molecu R2 NHCOOCH2CH2Si(CH3) R2 COOH lar sieves. A compound of formula (I) where R represents an optionally substituted C. alkylimino group may be used to form a different compound of formula (I) by reduction of the 25 ( \ - imine bond by a Suitable reducing agent, for example, sodium YN R5 YN R5 borohydride, in a suitable solvent, typically ethanol. Compounds of formula (I) where R is a derivatised amino R1 R1 group can be further manipulated depending on the desired (VII) (VI) derivatisation. For example N-alkenyl derivatives may be 30 oxidatively cleaved to produce aldehydes understandard con ditions. Such aldehyde derivatives may be further manipu lated to give other derivatives, e.g. reductive amination under standard conditions to give secondary and tertiary amines. Also, reaction of compounds of formula (I) in which R is 35 NH, with an acid chloride oran acid anhydride in an aprotic Solvent. Such as acetonitrile at reflux overnight, produces a compound of formula (I) in which R is NHR'' and R' represents an optionally substituted C. alkanoyl or C. (II) alkoxycarbonyl group. Alternatively, the reaction may take 40 place coupling a carboxylic acid with an amine in the pres A compound of formula (IV) may be obtained from a ence of a suitable coupling agent Such as a water-soluble compound of formula (III) by conventional halogenation pro carbodiimide. cedures, e.g. treatment of N-iodosuccinimide in a Suitable A compound of formula (I) in which R is NH, can Solvent such as acetonitrile to give the iodo compound. A undergo reaction with a tri-alkyl orthoformate, e.g. triethyl 45 compound of formula (IV) may be carbonylated using con orthoformate, in acidic conditions, by heating at elevated ventional procedures to give a compound of formula (V), e.g., temperatures, typically 60°C., for several hours, typically 2 using a palladium catalyst. Saponification of the methyl ester, to 4 hours, to give compounds of formula (I) in which R is a of formula (V), to give the acid, of formula (VI), may be methylimino group, Substituted by an optionally substituted achieved using standard ester hydrolysis conditions. A com C. alkoxy group, e.g. ethoxy. These imino-ethers can be 50 refluxed with primary or secondary amines optionally in a pound of formula (VII) may be prepared from a compound of suitable solvent to give other compounds of formula (I) formula (VI) by the Curtius rearrangement of the acyl azide wherein R is a methylimino group, Substituted by a di-C- prepared in situ by conventional procedures, e.g., diphe alkyl amino group, e.g. dimethylamino. nylphosphoryl azide is added dropwise to a solution of a A compound of formula (I) in which R is H, may be 55 compound of formula (VI), triethylamine and 2-(trimethylsi prepared by the diazotisation of a compound of formula (I) in lyl)ethanol in 1,4-dioxane at elevated temperature. Deprotec which R is NH by a variety of standard diazotisation pro tion to yield the amine of formula (II) may be effected using cedures. a variety of fluoride induced desilylation procedures, such as Compounds of formula (I) in which R is NH, can be heating a solution of a compound of formula (VII) and tet converted to give a compound of formula (I) wherein R is 60 rabutylammonium fluoride in a Suitable solvent, typically halo, utilising standard Sandmeyer reaction conditions. tetrahydrofuran, at elevated temperatures. Compounds of formula (I) in which R is NH can also be An alternative route to compounds of formula (II) is via converted to carbamates or ureas under standard conditions. nitration of compounds of formula (III) to give nitro com Halo-substituted carbamates may be further reacted with pounds of formula (VIII) followed by reduction of the nitro nucleophiles such as primary or secondary amines in a Suit 65 substituent of compounds of formula (VIII) to the amines of able alcoholic solvent, optionally with the addition of lithium formula (II) as shown in Scheme 2, wherein R, R and Rare iodide and allowing to stir at room temperature for several as previously defined for compounds of formula (I). US 7,687,533 B2 19 20 Sodium nitrite in an acidic mixture, for example glacial acetic acid and sulphuric acid at temperatures between 5-60° C. to Scheme 2 give the diazonium salt of formula (XII) R2 H R2 NO 5 W f (XI) e- NS \ e R-NH N R5 N R5 (XII) -- k k 10 RI-NEN (III) (VIII) R2 NH2 followed by reduction of the diazonium salt of formula (XII) with an agent Such as Stannous chloride in a concentrated acid ( ) 15 Such as hydrochloric acid. N R5 Alternatively, a compound of formula (XIII) R1 (II) (XIII) O The preparation of compounds of formula (VIII), wherein R2 O R", R and Rare as previously defined for formula (I), may \ be effected by conventional electrophilic nitration proce dures, then reduction of compounds of formula (VIII) may be 25 ( \ facilitated by a variety of reducing agents including those N1 YNH, described in “Handbook of Reagents for Organic Synthesis— k Oxidising and Reducing Agents' edited by S.D.Burke and R. L. Danheiser. 30 Compounds of formula (III) and (VIII) are useful com where R represents an optionally substituted Calkyl and pounds to undergo functional group interconversion at, for the methyl group is illustrative of any suitable carboxylic example, position R to give different groups of formula ester protecting group, may be prepared from a hydrazine of (VIII) using transformations herein described and obvious to formula (IX) and a compound of formula (XIV) those skilled in the art. 35 The preparation of a compound of formula (III) may be (XIV) achieved by the reduction of a compound of formula (IV), R2 COCH3 wherein halo is iodo, e.g. by transmetallation with a suitable organometallic reagent Such as a Grignard reagent, typically 40 isopropylmagnesium chloride, in a Suitable solvent Such as tetrahydrofuran at reduced temperature, under Suitable aque ous work-up conditions. wherein L is a leaving group, typically Cl, in a suitable sol Synthesis of the arylpyrazole template can be readily per 45 vent, typically diethyl ether, and a Suitable base Such as potas formed. sium carbonate. A compound of formula (III) wherein R is C, alkyl A compound of formula (III), wherein R is hydrogen, C. optionally Substituted by halo or Cs cycloalkyl may be pre alkyl optionally Substituted by halo or Cs cycloalkyl, may be pared from a hydrazine of formula (IX) by reaction with a prepared by reaction of a compound of formula (IX) with a C-cyanoketone of formula (X) 50 compound of formula (XV),

(IX) R-N-NH. (XV) (X) 55 O 1. R2 lus 60 wherein R is hydrogen, Calkyl optionally substituted by wherein R represents C, alkyl optionally substituted by halo or Cs cycloalkyl, and L is a leaving group Such as halo or Cs cycloalkyl, at elevated temperatures. Compounds chloro, bromo, iodo, at elevated temperatures. of formula (X) are well-known or can be prepared by methods A compound of formula (V) where R represents C, well-known to those skilled in the art. 65 alkyl, Chaloalkyl, Cs cycloalkyl or cyano may be pre A compound of formula (IX) may be prepared by diazoti pared by reaction of a compound of formula (IX) with a sation of a compound of formula (XI), by reaction with compound of formula (XVI) US 7,687,533 B2 21 22 An arylpyrazole compound of formula (XX), (XVI) CN (XX) O

C COMe CHS V ( \ wherein R represents C, alkyl, Chaloalkyl, Cs N1 YNH, cycloalkyl or cyano, in aprotic solvents such as diethyl ether 10 in the presence of a mild base such as potassium carbonate. k Chloroalkenes of formula (XVI) are obtained by chlorina tion of alkenes of formula (XVII) using phosphorous pen where R' is previously defined and the methyl group is illus tachloride in a solvent Such as dichloromethane at room tem 15 trative of any carboxylic acid protecting group, may be pre perature. pared by reaction of a hydrazine of formula (IX) with an electrophile such as a compound of formula (XXI) (XVII) R2 CN (XXI)

ON COMe S COCH3

Functionalised alkenes of formula (XVII) may be synthe 25 S CN sised using a wide variety of literature methodology. Alternatively, compounds of formula (III), where R rep resents CN and R represents OH or NH can be synthesised via the Japp-Klingemann reaction: the reaction of aryl diazo in an aprotic solvent, such as isopropyl alcohol, at reflux for nium salts of formula (IX) with compounds of formula 30 several hours. (XVIII) or (XIX), wherein R and R" are alkyl groups. The synthesis of the desired 1-aminobenzenes can be achieved using standard conditions. For example, 2,6-unsub stituted aniline derivatives can be mono- or di-chlorinated by (XVIII) the addition of N-chlorosuccinimide in a suitable solvent, NC CN 35 Such as acetonitrile, and heating at elevated temperatures, typically 45-50° C., for several hours, typically from 1 to 3 RO hours. Moreover, persons skilled in the art will be aware of varia O tions of, and alternatives to, the processes described which (XIX) 40 allow the compounds defined by formula (I) to be obtained. R"O It will also be appreciated by persons skilled in the art that, NC O within certain of the processes described, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of other functional groups RO 45 present in a particular substrate, the availability of key inter O mediates, and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent for use in the said synthetic steps. It will also be The diazonium salts of formula (IX) are typically gener appreciated that various standard Substituent or functional ated in situ, for example by the dropwise addition of a solution 50 group interconversions and transformations within certain of the aminobenzenes of formula (VIII) in glacial acetic acid compounds of formula (I) will provide other compounds of to a solution of Sodium nitrite in concentrated Sulphuric/ formula (I). glacial acetic acid mixtures at reduced temperature, typically The skilled person will appreciate that the compounds of 10° C., followed by heating at 50° C. for several hours, the invention could be made by methods other than those typically 1 hour and allowing to cool to room temperature. 55 herein described, by adaptation of the methods herein This solution of the diazonium salt is then added dropwise to described and/or adaptation of methods known in the art, for a solution of a compound of formula (XVIII) or (XIX) in a example the art described herein, or using standard textbooks Suitable solvent, such as acetic acid followed by Stirring at Such as “Comprehensive Organic Transformations—A room temperature for up to 1 hour. The reaction mixture is Guide to Functional Group Transformations, RC Larock, poured into water and extracted with a water immiscible 60 Wiley-VCH (1999 or later editions), “March's Advanced organic solvent such as dichloromethane. Aqueous ammo Organic Chemistry—Reactions, Mechanisms and Struc nium hydroxide is added to the organic extract and stirred ture', M B Smith, J. March, Wiley, (5th edition or later) overnight to give compounds of formula (III). “Advanced Organic Chemistry, Part B. Reactions and Syn Compounds of formula (XIX) can be prepared by the addi thesis’, FA Carey, RJ Sundberg, Kluwer Academic/Plenum tion of glycolonitrile to alpha-nitrite esters in a Suitable sol 65 Publications, (2001 or later editions), “Organic Synthesis— vent, in the presence of a mild base, typically, potassium The Disconnection Approach”, S Warren (Wiley), (1982 or carbonate, and stirred for several hours at room temperature. later editions), “Designing Organic Syntheses' S Warren US 7,687,533 B2 23 24 (Wiley) (1983 or later editions), “Guidebook To Organic Syn Included within the scope of the invention are complexes thesis RK Mackie and DMSmith (Longman) (1982 or later Such as clathrates, drug-host inclusion complexes wherein, in editions), etc., and the references therein as a guide. contrast to the aforementioned Solvates, the drug and host are It is to be understood that the synthetic transformation present in Stoichiometric or non-stoichiometric amounts. methods mentioned herein are exemplary only and they may 5 Also included are complexes of the drug containing two or be carried out in various different sequences in order that the more organic and/or inorganic components which may be in desired compounds can be efficiently assembled. The skilled Stoichiometric or non-stoichiometric amounts. The resulting chemist will exercise his judgment and skill as to the most complexes may be ionised, partially ionised, or non-ionised. efficient sequence of reactions for synthesis of a given target For a review of such complexes, see J Pharm Sci, 64 (8), compound. For example, Substituents may be added to and/or 10 1269-1288 by Haleblian (August 1975). chemical transformations performed upon, different interme Hereinafter all references to compounds of formula (I) diates to those mentioned hereinafter in conjunction with a include references to Salts, Solvates and complexes thereof particular reaction. This will depend interalia on factors such and to Solvates and complexes of salts thereof. as the nature of other functional groups present in a particular The compounds of the invention include compounds of substrate, the availability of key intermediates and the pro 15 formula (I) as hereinbefore defined, and all polymorphs and tecting group strategy (if any) to be adopted. Clearly, the type prodrugs thereof. The invention also includes all isomers of of chemistry involved will influence the choice of reagent that the compounds of formula (I) (including optical, geometric is used in the said synthetic steps, the need, and type, of and tautomeric isomers) as hereinafter defined and isotopi protecting groups that are employed, and the sequence for cally-labeled compounds of formula (I). accomplishing the synthesis. The procedures may be adapted Within the scope of the invention are so-called prodrugs as appropriate to the reactants, reagents and other reaction of the compounds of formula (I). Thus certain derivatives of parameters in a manner that will be evident to the skilled compounds of formula (I) which may have little or no phar person by reference to standard textbooks and to the examples macological activity themselves can, when administered into provided hereinafter. or onto the body, be converted into compounds of formula (I) It will be apparent to those skilled in the art that sensitive 25 having the desired activity, for example, by hydrolytic cleav functional groups may need to be protected and deprotected age. Such derivatives are referred to as prodrugs. It will be during synthesis of a compound of the invention. This may be appreciated that certain compounds of formula (I) may them achieved by conventional methods, for example as described selves act as prod-drugs of other compounds of formula (I). in “Protective Groups in Organic Synthesis” by TW Greene Further information on the use of prodrugs may be found in and P G M Wuts, John Wiley & Sons Inc (1999), and refer 30 Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Sympo ences therein. sium Series (T Higuchi and W Stella) and Bioreversible Pharmaceutically acceptable salts of the compounds of Carriers in Drug Design, Pergamon Press, 1987 (ed. E B formula (I) include the acid addition and base salts thereof for Roche, American Pharmaceutical Association). compounds of Sufficient acidity or basisity. Prodrugs in accordance with the invention can, for Suitable acid addition salts are formed from acids which 35 example, be produced by replacing the 5-amino Substituent form non-toxic salts. Examples include the acetate, aspartate, on the pyrazole ring in the compounds of formula (I) with benzoate, besylate, bicarbonate/carbonate, bisulphate/sul certain moieties known to those skilled in the art as pro-drug phate, borate, camsylate, citrate, edisylate, esylate, formate, moieties as described, for example, in “Design of Prodrugs' fumarate, gluceptate, gluconate, glucuronate, hexafluoro by H Bundgaard (Elsevier, 1985); "Design and application of phosphate, hibenzate, hydrochloride/chloride, hydrobro 40 prodrugs.” Textbook of Drug Design and Discovery, (3" Edi mide/bromide, hydroiodide/iodide, isethionate, lactate, tion), 2002, 410-458, (Taylor and Francis Ltd., London); and malate, maleate, malonate, mesylate, methylsulphate, naph references therein. thylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate? dihydro Suitable prodrugs may have an N-containing group at the 5-position of the pyrazole ring of formula (I) and are bound to gen phosphate, Saccharate, Stearate. Succinate, tartrate, tosy 45 late and trifluoroacetate salts. the ring through N. The 5-N group can be substituted once or Suitable base salts are formed from bases which form twice. Examples of Substituents include: alkyl amines, aryl amines, amides, ureas, carbamates, cyclic carbamates, imi non-toxic salts. Examples include the aluminium, arginine, nes, enamines, imides, cyclic imides, Sulfenamides, and Sul benZathine, calcium, choline, diethylamine, diolamine, gly fonamides. The hydrocarbon portion of these groups contain cine, lysine, magnesium, meglumine, olamine, potassium, 50 C. alkyl, phenyl, heteroaryl Such as pyridyl, C- alkenyl, Sodium, tromethamine and Zinc salts. and Cs cycloalkyl, wherein each of the above groups may For a review on suitable salts, see “Handbook of Pharma include one or more optional Substituents where chemically ceutical Salts: Properties, Selection, and Use' by Stahl and possible independently selected from: halo: hydroxy: C Wermuth (Wiley-VCH. Weinheim, Germany, 2002). alkyl and C alkoxy. A pharmaceutically acceptable salt of a compound of for 55 mula (I) may be readily prepared by mixing together solu Further examples of replacement groups in accordance tions of the compound of formula (I) and the desired acid or with the foregoing example and examples of other prodrug base, as appropriate. The salt may precipitate from Solution types may be found in the aforementioned references. and be collected by filtration or may be recovered by evapo A prodrug according to the invention can be readily iden ration of the solvent. The degree of ionisation in the salt may 60 tified by administering it to a test animal and sampling a body vary from completely ionised to almost non-ionised. fluid for a compound of formula (I). The compounds of the invention may exist in both unsol Compounds of formula (I) containing one or more asym vated and solvated forms. The term solvate is used hereinto metric carbon atoms can exist as two or more stereoisomers. describe a molecular complex comprising the compound of Where a compound of formula (I) contains an alkenyl or the invention and one or more pharmaceutically acceptable 65 alkenylene group, geometric cis/trans (or Z/E) isomers are solvent molecules, for example, ethanol. The term hydrate is possible. Where the compound contains, for example, a keto employed when said solvent is water. or oxime group or an aromatic moiety, tautomeric isomerism US 7,687,533 B2 25 26 (tautomerism) can occur. It follows that a single compound those skilled in the art or by processes analogous to those may exhibit more than one type of isomerism. described in the accompanying Examples and Preparations Included within the scope of the present invention are all using an appropriate isotopically-labeled reagents in place of Stereoisomers, geometric isomers and tautomeric forms of the non-labeled reagent previously employed. the compounds of formula (I), including compounds exhib 5 Pharmaceutically acceptable Solvates in accordance with iting more than one type of isomerism, and mixtures of one or the invention include those wherein the solvent of crystalli more thereof. Also included are acid addition or base salts zation may be isotopically substituted, e.g. DO, de-acetone, wherein the counterion is optically active, for example, d-DMSO. Compounds of the invention intended for phar D-lactate or L-lysine, or racemic, for example, DL-tartrate or maceutical use may be administered as crystalline or amor DL-arginine. 10 phous products. They may be obtained, for example, as Solid Cis/trans isomers may be separated by conventional tech plugs, powders, or films by methods such as precipitation, niques well known to those skilled in the art, for example, crystallization, freeze drying, spray drying, or evaporative chromatography and fractional crystallisation. drying. Microwave or radio frequency drying may be used for Conventional techniques for the preparation/isolation of this purpose. individual enantiomers include chiral synthesis from a Suit 15 They may be administered alone or in combination with able optically pure precursor or resolution of the racemate (or one or more other compounds of the invention or in combi the racemate of a salt or derivative) using, for example, chiral nation with one or more other drugs (or as any combination high pressure liquid chromatography (HPLC). thereof). Alternatively, the racemate (or a racemic precursor) may be Compounds of this invention can also be mixed with one or reacted with a suitable optically active compound, for more biologically active compounds or agents including example, an alcohol, or, in the case where the compound of insecticides, acaricides, anthelmintics, fungicides, nemato formula (I) contains an acidic or basic moiety, an acid or base cides, antiprotozoals, bactericides, growth regulators, ento Such as tartaric acid or 1-phenylethylamine. The resulting mopathogenic bacteria, viruses or fungi to form a multi diastereomeric mixture may be separated by chromatography component pesticide giving an even broader spectrum of and/or fractional crystallization and one or both of the dias 25 pharmaceutical, Veterinary or agricultural utility. Thus the tereoisomers converted to the corresponding pure present invention also pertains to a composition comprising a enantiomer(s) by means well known to a skilled person. biologically effective amount of compounds of the invention Chiral compounds of the invention (and chiral precursors and an effective amount of at least one additional biologically thereof) may be obtained in enantiomerically-enriched form active compound or agent and can further comprise one or using chromatography, typically HPLC, on an asymmetric 30 more of Surfactant, a Solid diluent or a liquid diluent. resin with a mobile phase consisting of a hydrocarbon, typi The following list of biologically active compounds cally heptane or hexane, containing from 0 to 50% isopro together with which the compounds of the invention can be panol, typically from 2 to 20%, and from 0 to 5% of an used is intended to illustrate the possible combinations, but alkylamine, typically 0.1% diethylamine. Concentration of not to impose any limitation. the eluate affords the enriched mixture. 35 Stereoisomeric conglomerates may be separated by con For example, compounds of the present invention may be ventional techniques known to those skilled in the art—see, co-administered or used in combination with anthelmintic for example, “Stereochemistry of Organic Compounds” by E agents. Such anthelmintic agents include, compounds L Eliel (Wiley, New York, 1994). selected from the macrocyclic lactone class of compounds The present invention includes all pharmaceutically 40 Such as ivermectin, avermectin, abamectin, emamectin, epri acceptable isotopically-labelled compounds of formula (I) nomectin, doramectin, Selamectin, moxidectin, nemadectin wherein one or more atoms are replaced by atoms having the and milbemycin derivatives as described in EP-357460, same atomic number, but an atomic mass or mass number EP-444964 and EP-594291. Additional anthelmintic agents different from the atomic mass or mass number usually found include semisynthetic and biosynthetic avermectin/milbemy in nature. 45 cinderivatives such as those described in U.S. Pat. No. 5,015, Examples of isotopes suitable for inclusion in the com 630, WO-9415944 and WO-9522552. Additional anthelm pounds of the invention include isotopes of hydrogen, Such as intic agents include the benzimidazoles such as albendazole, 'Hand H. carbon, such as 'C, 'Cand ''C, chlorine, such as cambendazole, fenbendazole, flubendazole, mebendazole, Cl, fluorine, such as 'F, iodine, such as 'I and 'I, oxfendazole, oxibendazole, parbendazole, and other mem nitrogen, such as 'N and 'N, oxygen, such as "O, O and 50 bers of the class. Additional anthelmintic agents include imi 'O, phosphorus, such as P. and sulphur, such as S. dazothiazoles and tetrahydropyrimidines Such as tetramisole, Certain isotopically-labelled compounds of formula (I), levamisole, pyrantel pamoate, oxantel or morantel. for example, those incorporating a radioactive isotope, are Compounds of this invention may also be used in combi useful in drug and/or substrate tissue distribution studies. The nation with derivatives and analogues of the paraherquamide/ radioactive isotopes tritium, i.e. H, and carbon-14, i.e. ''C, 55 marcfortine class of anthelmintic agents, as well as the anti are particularly useful for this purpose in view of their ease of parasitic oxazolines such as those disclosed in U.S. Pat. No. incorporation and ready means of detection. 5,478,855, U.S. Pat. No. 4,639,771 and DE-19520936. Substitution with heavier isotopes such as deuterium, i.e. Compounds of this invention may be co-administered or *H, may afford certain therapeutic advantages resulting from used in combination with derivatives and analogues of the greater metabolic stability, for example, increased in vivo 60 general class of dioxomorpholine antiparasitic agents as half-life or reduced dosage requirements, and hence may be described in WO-96.15121 and also with anthelmintic active preferred in some circumstances. cyclic depsipeptides such as those described in WO-961 1945, Substitution with positron emitting isotopes, such as 'C, WO-931.9053, WO-9325543, EP-626375, EP-382173, 'F, 'O and 'N, can be useful in Positron Emission Topog WO-94.19334, EP-382173, and EP-503538. raphy (PET) studies for examining substrate receptor occu 65 Compounds of this invention may be co-administered or pancy. Isotopically-labeled compounds of formula (I) can used in combination with other ectoparasiticides; for generally be prepared by conventional techniques known to example, fipronil; pyrethroids; organophosphates; insect US 7,687,533 B2 27 28 growth regulators such as lufenuron; ecdysone agonists Such R-195, RH-0345, RH-2485, RYI-210, S-1283, S-1833, as tebufenozide and the like; neonicotinoids such as imida SI-8601, silafluofen, silomadine, spinosad, tebufenpyrad, cloprid and the like. tetradifon, tetranactin, thiacloprid, thiocyclam, thia Other examples of Such biologically active compounds methoxam, tolfenpyrad, triaZamate, triethoxyspinosyn, tri include but are not restricted to the following: nactin, verbutin, vertialec, YI-5301 Organophosphates: acephate, azamethiphos, azinphos-ethyl, Fungicides: acibenzolar, aldimorph, ampropylfos, andoprim, azinphos-methyl, bromophos, bromophos-ethyl, aZaconazole, azoxystrobin, benalaxyl, benomyl, biala cadusafos, chlorethoxyphos, chlorpyrifos, chlorfenVin phos, blasticidin-S, Bordeaux mixture, bromuconazole, phos, chlormephos, demeton, demeton-5-methyl, deme bupirimate, carpropamid, captafol, captan, carbendazim, ton-5-methyl Sulphone, dialifos, diazinon, dichlorvos, 10 chlorfenazole, chloroneb, chloropicrin, chlorothalonil, dicrotophos, dimethoate, disulfoton, ethion, ethoprophos, chloZolinate, copper oxychloride, copper salts, cyflufena etrimfos, famphur, fenamiphos, fenitrothion, fensul mid, cymoxanil, cyproconazole, cyprodinil, cyprofuram, fothion, fenthion, flupyrazofos, fonofos, formothion, fos RH-7281, diclocymet, diclobutrazole, diclomezine, diclo thiazate, heptenophos, isaZophos, isothioate, isoxathion, ran, difenoconazole, RP-407213, dimethomorph, domox malathion, methacriphos, methamidophos, methidathion, 15 yStrobin, diniconazole, diniconazole-M, dodine, edifen methyl-parathion, mevinphos, monocrotophos, naled, phos, epoxiconazole, famoxadone, fenamidone, omethoate, oxydemeton-methyl, paraoxon, parathion, par fenarimol, fenbuconazole, fencaramid, fenpiclonil, fen athion-methyl, phenthoate, phosalone, phosfolan, phos propidin, fenpropimorph, fentin acetate, fluaZinam, flu phocarb, phosmet, phosphamidon, phorate, phoxim, pir dioxonil, flumetover, flumorf/flumorlin, fentin hydroxide, imiphos, pirimiphos-methyl, profenofos, propaphos, fluoxastrobin, flucuinconazole, flusilazole, flutolanil, flu proetamphos, prothiofos, pyraclofos, pyridapenthion, triafol, folpet, fosetyl-aluminium, furalaxyl, furametapyr, quinalphos, Sulprophos, temephos, terbufos, tebupirimfos, hexaconazole, ipconazole, iprobenfos, iprodione, isopro tetrachlorvinphos, thimeton, triaZophos, trichlorfon, Vami thiolane, kasugamycin, krSoxim-methyl, mancoZeb, dothion. maneb, mefenoxam, mepronil, metalaxyl, metconazole, Carbamates: alanycarb, aldicarb, 2-sec-butylphenyl methyl 25 metominostrobin/fenominostrobin, metrafenone, carbamate, benfuracarb, carbaryl, carbofuran, carbosulfan, myclobutanil, neo-asozin, nicobifen, orysastrobin, oxa cloethocarb, ethiofencarb, fenoxycarb, fenthiocarb, dixyl, penconazole, pencycuron, probenazole, prochloraz, furathiocarb, HCN-801, isoprocarb, indoxacarb, methio propamocarb, propioconazole, produinazid, prothiocona carb, methomyl, 5-methyl-m-cumenylbutyryl(methyl)car Zole, pyrifenox, pyraclostrobin, pyrimethanil, pyroquilon, bamate, oxamyl, pirimicarb, propoXur, thiodicarb, thio 30 quinoxyfen, spiroxamine, Sulfur, tebuconazole, tetrcona fanox, triazamate, UC-51717 Zole, thiabendazole, thifluzamide, thiophanate-methyl, Pyrethroids: acrinathin, allethrin, alphametrin, 5-benzyl-3- thiram, tiadinil, triadimefon, triadimenol, tricyclazole, tri furylmethyl (E)-(1R)-cis-2,2-dimethyl-3-(2-oxothiolan-3- floxystrobin, triticonazole, validamycin, Vinclozin ylidenemethyl)cyclopropanecarboxylate, bifenthrin, B-cy Biological agents: Bacillus thuringiensis ssp aizawai, fluthrin, cyfluthrin, C-cypermethrin, B-cypermethrin, 35 kurstaki, Bacillus thuringiensis delta endotoxin, baculovi bioallethrin, bioallethrin((S)-cyclopentylisomer), biores rus, entomopathogenic bacteria, virus and fungi methrin, bifenthrin, NCI-85193, cycloprothrin, cyhalo thrin, cythithrin, cyphenothrin, deltamethrin, empenthrin, Bactericides: chlortetracycline, oxytetracycline, Streptomy esfenvalerate, ethofenprox, fenfluthrin, fempropathrin, fen cin, Valerate, flucythrinate, flumethrin, fluvalinate (D isomer), 40 Generally, they will be administered as a formulation in imiprothrin, cyhalothrin, w-cyhalothrin, permethrin, phe association with one or more pharmaceutically acceptable nothrin, prallethrin, pyrethrins (natural products), res excipients. The term “excipient' is used herein to describe methrin, tetramethrin, transfluthrin, theta-cypermethrin, any ingredient other than the compound(s) of the invention. silafluofen, T-fluvalinate, tefluthrin, tralomethrin, Zeta The choice of excipient will to a large extent depend on cypermethrin. 45 factors such as the particular mode of administration, the Arthropod growth regulators: a) chitin synthesis inhibitors: effect of the excipient on solubility and stability, and the benzoylureas: chlorfluaZuron, diflubenzuron, fluaZuron, nature of the dosage form. The compounds of the invention flucycloXuron, flufenoXuron, hexaflumuron, lufenuron, are of particular value in the control of parasites which are novaluron, teflubenzuron, triflumuron, buprofezin, injurious to, or spread oract as vectors of diseases in, man and diofenolan, hexythiazox, etoxazole, chlorfentazine; b) 50 domestic animals, for example those hereinbefore men ecdysone antagonists: halofenozide, methoxyfenozide, tioned, and more especially in the control of ticks, mites, lice, tebufenozide; c) juvenoids: pyriproxyfen, methoprene, fleas, midges and biting, nuisance and myiasis flies. They are fenoxycarb; d) lipid biosynthesis inhibitors: spirodiclofen particularly useful in controlling arthropods which are Other antiparasitics: acequinocyl, amitraz, AKD-1022, ANS present inside domestic host animals or which feed in or on 118, azadirachtin, Bacillus thuringiensis, benSultap, 55 the skin or suck the blood of the animal, for which purpose bifenazate, binapacryl, bromopropylate, BTG-504, BTG they may be administered orally, parenterally, percutaneously 505, camphechlor, cartap, chlorobenzilate, chlordime or topically. form, chlorfenapyr, chromafenozide, clothianidine, cyro Pharmaceutical compositions suitable for the delivery of mazine, diacloden, diafenthiuron, DBI-3204, dinactin, compounds of the present invention and methods for their dihydroxymethyldihydroxypyrrolidine, dinobuton, 60 preparation will be readily apparent to those skilled in the art. dinocap, endosulfan, ethiprole, ethofenproX, fenaZaquin, Such compositions and methods for their preparation may be flumite, MTI-800, fenpyroximate, fluacrypyrim, flubenz found, for example, in Remington's Pharmaceutical Sci imine, flubrocythrinate, flufenzine, flufenprox, fluproxy ences, 19th Edition (Mack Publishing Company, 1995). fen, halofenprox, hydramethylnon, IKI-220, kanemite, With respect to their use in mammals, the compounds may NC-196, neem guard, nidinorterfuran, nitenpyram, 65 be administered alone or in a formulation appropriate to the SD-35651, WL-108477, pirydaryl, propargite, protrifen specific use envisaged, the particular species of host mammal bute, pymethrozine, pyridaben, pyrimidifen, NC-1 111, being treated and the parasite involved. US 7,687,533 B2 29 30 The compounds of the invention may be administered extruded before tabletting. The final formulation may com orally. Oral administration may involve Swallowing, so that prise one or more layers and may be coated or uncoated; it the compound enters the gastrointestinal tract, or buccal or may even be encapsulated. Sublingual administration may be employed by which the The formulation of tablets is discussed in “Pharmaceutical compound enters the blood stream directly from the mouth. Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Formulations suitable for oral administration include solid Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247 formulations such as tablets, capsules containing particulates, 6918-X). liquids, or powders, lozenges (including liquid-filled), chews, Solid formulations for oral administration may be formu multi- and nano-particulates, gels, Solid solution, liposome, lated to be immediate and/or modified release. Modified films (including muco-adhesive), ovules, sprays and liquid 10 release formulations include delayed-, Sustained-, pulsed formulations. controlled-, targeted and programmed release. Liquid formulations include Suspensions, solutions, syrups Suitable modified release formulations for the purposes of and elixirs. Such formulations may be employed as fillers in the invention are described in U.S. Pat. No. 6,106,864. Details Soft or hard capsules and typically comprise a carrier, for of other Suitable release technologies such as high energy example, water, ethanol, polyethylene glycol, propylene gly 15 dispersions and osmotic and coated particles are to be found col, methylcellulose, or a suitable oil, and one or more emul in Verma et al., Pharmaceutical Technology On-line, 25(2), Sifying agents and/or Suspending agents. Liquid formulations 1-14 (2001). may also be prepared by the reconstitution of a solid, for The compounds of the invention may also be administered example, from a Sachet. directly into the blood stream, into muscle, or into an internal The compounds of the invention may also be used in fast organ. Suitable means for parenteral administration include dissolving, fast-disintegrating dosage forms such as those bolus, intravenous, intraarterial, intraperitoneal, intrathecal, described in Expert Opinion in Therapeutic Patents, 11(6), intraventricular, intraurethral, intrasternal, intracranial, intra 981-986 by Liang and Chen (2001). muscular and Subcutaneous. Suitable devices for parenteral For tablet dosage forms, depending on dose, the drug may administration include needle (including microneedle) injec make up from 1 wt % to 80 wt % of the dosage form, more 25 tors, needle-free injectors and infusion techniques. typically from 5 wt % to 60 wt % of the dosage form. In Parenteral formulations are typically aqueous solutions addition to the drug, tablets generally contain a disintegrant. which may contain excipients such as salts, carbohydrates Examples of disintegrants include Sodium starch glycolate, and buffering agents (preferably to a pH of from 3 to 9), but, Sodium carboxymethyl cellulose, calcium carboxymethyl for some applications, they may be more Suitably formulated cellulose, croScarmellose Sodium, crospovidone, polyvi 30 as a sterile non-aqueous solution or as a dried form to be used nylpyrrolidone, methyl cellulose, microcrystalline cellulose, in conjunction with a suitable vehicle Such as sterile, pyro lower alkyl-substituted hydroxypropyl cellulose, starch, gen-free water. pregelatinised starch and Sodium alginate. Generally, the dis The preparation of parenteral formulations under sterile integrant will comprise from 1 wt % to 25 wt %, preferably conditions, for example, by lyophilisation, may readily be from 5 wt % to 20 wt % of the dosage form. 35 accomplished using standard pharmaceutical techniques well Binders are generally used to impart cohesive qualities to a known to those skilled in the art. tablet formulation. Suitable binders include microcrystalline The solubility of compounds of formula (I) used in the cellulose, gelatin, Sugars, polyethylene glycol, natural and preparation of parenteral Solutions may be increased by the synthetic gums, polyvinylpyrrolidone, pregelatinised starch, use of appropriate formulation techniques, such as the incor hydroxypropyl cellulose and hydroxypropyl methylcellu 40 poration of Solubility-enhancing agents. lose. Tablets may also contain diluents, such as lactose Formulations for parenteral administration may be formu (monohydrate, spray-dried monohydrate, anhydrous and the lated to be immediate and/or modified release. Modified like), mannitol, Xylitol, dextrose, Sucrose, Sorbitol, microc release formulations include delayed-, Sustained-, pulsed rystalline cellulose, starch and dibasic calcium phosphate controlled-, targeted and programmed release. Thus com dihydrate. 45 pounds of the invention may be formulated as a solid, semi Tablets may also optionally comprise Surface active agents, Solid, or thixotropic liquid for administration as an implanted Such as Sodium lauryl Sulfate and polysorbate 80, and glidants depot providing modified release of the active compound. Such as silicon dioxide and talc. When present, Surface active Examples of Such formulations include drug-coated Stents agents may comprise from 0.2 wt % to 5 wt % of the tablet, and PGLA microspheres. and glidants may comprise from 0.2 wt % to 1 wt % of the 50 The compounds of the invention may also be administered tablet. topically to the skin or mucosa, that is, dermally or transder Tablets also generally contain lubricants such as magne mally. Typical formulations for this purpose include sium Stearate, calcium Stearate, Zinc Stearate, sodium Stearyl drenches, gels, hydrogels, lotions, Solutions, creams, oint fumarate, and mixtures of magnesium Stearate with sodium ments, dusting powders, dressings, foams, films, skin lauryl Sulphate. Lubricants generally comprise from 0.25 wt 55 patches, wafers, implants, sponges, fibres, bandages and % to 10 wt %, preferably from 0.5 wt % to 3 wt % of the tablet. microemulsions. Liposomes may also be used. Typical carri Other possible ingredients include anti-oxidants, colou ers include alcohol, water, mineral oil, liquid petrolatum, rants, flavouring agents, preservatives and taste-masking white petrolatum, glycerin, polyethylene glycol and propy agents. lene glycol. Penetration enhancers may be incorporated— Exemplary tablets contain up to about 80% drug, from 60 see, for example, J Pharm Sci., 88 (10),955-958 by Finnin and about 10 wt % to about 90 wt % binder, from about 0 wt % to Morgan (October 1999). Pour-on or spot-on formulations about 85 wt % diluent, from about 2 wt % to about 10 wt % may be prepared by dissolving the active ingredient in an disintegrant, and from about 0.25 wt % to about 10 wt % acceptable liquid carrier vehicle Such as butyl digol, liquid lubricant. paraffin or a non-volatile ester, optionally with the addition of Tablet blends may be compressed directly or by roller to 65 a volatile component such as propan-2-ol. Alternatively, form tablets. Tablet blends or portions of blends may alterna pour-on, spot-on or spray formulations can be prepared by tively be wet-, dry-, or melt-granulated, melt congealed, or encapsulation, to leave a residue of active agent on the Surface US 7,687,533 B2 31 32 of the animal. Injectable formulations may be prepared in the typically arranged to administer a metered dose or “puff form of a sterile solution which may contain other Substances, containing from 1 to 1000 ug of the compound of formula (I). for example enough salts or glucose to make the Solution The overall daily dose will typically be in the range 100 ug to isotonic with blood. 100 mg which may be administered in a single dose or, more Other means of topical administration include delivery by usually, as divided doses throughout the day. electroporation, iontophoresis, phonophoresis, Sonophoresis The compounds of the invention may be administered rec and microneedle or needle-free (e.g. PowderjectTM, tally or vaginally, for example, in the form of a Suppository, BiojectTM, etc.) injection. pessary, or enema. Cocoa butter is a traditional Suppository Formulations for topical administration may beformulated base, but various alternatives may be used as appropriate. to be immediate and/or modified release. Modified release 10 Formulations for rectal/vaginal administration may be for formulations include delayed-, Sustained-, pulsed-, con mulated to be immediate and/or modified release. Modified trolled-, targeted and programmed release. release formulations include delayed-, Sustained-, pulsed The compounds of the invention can also be administered controlled-, targeted and programmed release. intranasally or by inhalation, typically in the form of a dry The compounds of the invention may also be administered powder (either alone, as a mixture, for example, in a dry blend 15 directly to the eye or ear, typically in the form of drops of a with lactose, or as a mixed component particle, for example, micronised Suspension or solution in isotonic, pH-adjusted, mixed with phospholipids, such as phosphatidylcholine) sterile saline. Otherformulations suitable for ocular and aural from a dry powder inhaler or as an aerosol spray from a administration include ointments, biodegradable (e.g. pressurised container, pump, spray, atomiser (preferably an absorbable gel sponges, collagen) and non-biodegradable atomiser using electrohydrodynamics to produce a fine mist), (e.g. silicone) implants, wafers, lenses and particulate or or nebuliser, with or without the use of a suitable propellant, vesicular systems. Such as niosomes or liposomes. A polymer such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluo Such as crossed-linked polyacrylic acid, polyvinylalcohol, ropropane. For intranasal use, the powder may comprise a hyaluronic acid, a cellulosic polymer, for example, hydrox bioadhesive agent, for example, chitosan or cyclodextrin. ypropylmethylcellulose, hydroxyethylcellulose, or methyl The pressurised container, pump, spray, atomizer, or nebu 25 cellulose, or a heteropolysaccharide polymer, for example, liser contains a solution or Suspension of the compound(s) of gelangum, may be incorporated together with a preservative, the invention comprising, for example, ethanol, aqueous etha Such as benzalkonium chloride. Such formulations may also nol, or a suitable alternative agent for dispersing, solubilising, be delivered by iontophoresis. or extending release of the active, a propellant(s) as solvent Formulations for ocular/aural administration may be for and an optional Surfactant, such as Sorbitan trioleate, oleic 30 mulated to be immediate and/or modified release. Modified acid, or an oligolactic acid. release formulations include delayed-, Sustained-, pulsed Prior to use in a dry powder or suspension formulation, the controlled-, targeted, or programmed release. drug product is micronised to a size suitable for delivery by The compounds of the invention may be combined with inhalation (typically less than 5 microns). This may be soluble macromolecular entities, such as cyclodextrin and achieved by any appropriate comminuting method, such as 35 suitable derivatives thereof or polyethylene glycol-contain spiral jet milling, fluid bed jet milling, Supercritical fluid ing polymers, in order to improve their solubility, dissolution processing to form nanoparticles, high pressure homogenisa rate, taste-masking, bioavailability and/or stability for use in tion, or spray drying. any of the aforementioned modes of administration. Capsules (made, for example, from gelatin or HPMC), Drug-cyclodextrin complexes, for example, are found to be blisters and cartridges for use in an inhaler or insufflator may 40 generally useful for most dosage forms and administration be formulated to contain a powder mix of the compound of routes. Both inclusion and non-inclusion complexes may be the invention, a Suitable powder base Such as lactose or starch used. As an alternative to direct complexation with the drug, and a performance modifier Such as 1-leucine, mannitol, or the cyclodextrin may be used as an auxiliary additive, i.e. as magnesium Stearate. The lactose may be anhydrous or in the a carrier, diluent, or solubiliser. Most commonly used for form of the monohydrate, preferably the latter. Other suitable 45 these purposes are alpha-, beta- and gamma-cyclodextrins, excipients include dextran, glucose, maltose, Sorbitol, Xylitol, examples of which may be found in International Patent fructose. Sucrose and trehalose. Applications Nos. WO 91/11172, WO 94/02518 and WO A Suitable solution formulation for use in anatomiser using 98/55148. electrohydrodynamics to produce a fine mist may contain Acceptable liquid carriers include vegetable oils such as from 1 Jug to 20 mg of the compound of the invention per 50 sesame oil, glycerides such as triacetin, esters such as benzyl actuation and the actuation volume may vary from 1 Jul to 100 benzoate, isopropyl myristate and fatty acid derivatives of ul. A typical formulation may comprise a compound of for propylene glycol, as well as organic solvents such as pyrro mula (I), propylene glycol, sterile water, ethanol and sodium lidin-2-one and glycerol formal. The formulations are pre chloride. Alternative solvents which may be used instead of pared by dissolving or Suspending the active ingredient in the propylene glycol include glycerol and polyethylene glycol. 55 liquid carrier Such that the final formulation contains from Suitable flavours, such as menthol and levomenthol, or 0.01 to 10% by weight of the active ingredient. Sweeteners, such as Saccharin or saccharin Sodium, may be Such formulations are prepared in a conventional manner added to those formulations of the invention intended for in accordance with standard medicinal or veterinary practice. inhaled/intranasal administration. These formulations will vary with regard to the weight of Formulations for inhaled/intranasal administration may be 60 active compound contained therein, depending on the species formulated to be immediate and/or modified release using, for of host animal to be treated, the severity and type of infection example, poly(DL-lactic-coglycolic acid (PGLA). Modified and the body weight of the host. For parenteral, topical and release formulations include delayed-, Sustained-, pulsed oral administration, typical dose ranges of the active ingredi controlled-, targeted and programmed release. ent are 0.01 to 100 mg per kg of body weight of the animal. In the case of dry powder inhalers and aerosols, the dosage 65 Preferably the range is 0.1 to 10 mg per kg. unit is determined by means of a valve which delivers a As an alternative the compounds may be administered to a metered amount. Units in accordance with the invention are non-human animal with the drinking water or feedstuff and US 7,687,533 B2 33 34 for this purpose a concentrated feed additive or premix may usually contain about 0.05 to about 95% (by weight) of one or be prepared for mixing with the normal animal feed or drink. more active ingredients according to the invention, about 1 to Inasmuch as it may desirable to administer a combination about 95% of one or more solid or liquid carriers and, option of active compounds, for example, for the purpose of treating ally, about 0.1 to about 50% of one or more other compatible a particular disease or condition, it is within the scope of the components, such as Surface-active agents or the like. present invention that two or more pharmaceutical composi In the present account, the term “carrier denotes an tions, at least one of which contains a compound in accor organic or inorganic ingredient, natural or synthetic, with dance with the invention, may conveniently be combined in which the active ingredient is combined to facilitate its appli the form of a kit suitable for coadministration of the compo cation. This carrier is therefore generally inert and it must be sitions. 10 acceptable (for example, agronomically acceptable, particu Thus the kit of the invention comprises two or more sepa larly to the treated plant). rate pharmaceutical compositions, at least one of which con The carrier may be a solid, for example, ground natural tains a compound of formula (I) in accordance with the inven minerals, such as attapulgite, bentonite, clays, chalk, diato tion, and means for separately retaining said compositions, maceous earth, kaolins, montmorillonite, quartz, or talc, such as a container, divided bottle, or divided foil packet. An 15 ground synthetic minerals, such as alumina, silica, or sili example of such a kit is the familiar blister pack used for the cates, naturalsilicates, silica, resins, waxes, or solid fertiliz packaging of tablets, capsules and the like. ers). As solid carriers for granules the following are Suitable: The kit of the invention is particularly suitable for admin crushed natural rocks such as calcite, dolomite, marble, pum istering different dosage forms, for example, oral and ice, and Sepiolite; synthetic granules of inorganic or organic parenteral, for administering the separate compositions at meals; granules of organic material Such as, coconut shells, different dosage intervals, or for titrating the separate com corn cobs, cornhusks or sawdust; absorbent carbon black, positions against one another. To assist compliance, the kit kieselguhr, or powdered cork; water soluble polymers, resins, typically comprises directions for administration and may be waxes; or Solid fertilizers. Such solid compositions may, if provided with a so-called memory aid. desired, contain one or more compatible wetting, dispersing, For administration to animal patients, the total daily dose 25 emulsifying or colouring agents which, when solid, may also of the compounds of the invention is typically in the range 0.1 serve as a diluent. mg/kg to 100 mg/kg depending, of course, on the mode of The carrier may also be liquid, for example: water, alco administration. For example, oral administration may require hols, particularly butanol or glycol, as well as their ethers or a total daily dose of from 0.5 mg/kg to 100 mg/kg, while an esters, particularly methyl glycol acetate; ketones, particu intravenous dose may only require from 0.1 mg/kg to 10 30 larly acetone, cyclohexanone, methylethyl ketone, methyl mg/kg. The total daily dose may be administered in single or isobutylketone, or isophorone; petroleum fractions such as divided doses. aliphatic or aromatic hydrocarbons, particularly Xylenes: The veterinarian will readily be able to determine doses for mineral or vegetable oils; chlorinated hydrocarbons, particu individual animals according to age, weight and need. larly trichloroethane, methylene chloride or chlorobenzenes: The compounds of the invention also have utility in the 35 water-soluble or strongly polar solvents such as dimethylfor control of plant pests, soil inhabiting pests and other environ mamide, dimethylsulphoxide, or N-methylpyrrolidone; or a mental pests. mixture thereof. Compositions Suitable for applications in agriculture, hor The Surface-active agent may be an emulsifying agent, ticulture include formulations suitable for use as, for dispersing agent or wetting agent of the ionic or non-ionic example, sprays, dusts, granules, fogs, foams, emulsions. The 40 type or a mixture of Such agents. The presence of at least one active compound is generally applied to the locus in which Surface-active agent is generally essential when the active arthropod or nematode infestation is to be controlled at a rate ingredient and/or the inert carrier are not or only slightly of about 0.02 kg to about 20 kg of active compound per water soluble and the carrier agent of the composition for hectare of locus treated. Adverse weather conditions, pest application is water. resistance and other factors may require that the active ingre 45 Compositions of the invention may further contain other dient be used in higher proportions. For foliar application, a additives such as adhesives or colorants. Adhesives such as rate of 0.01 to 1 kg/ha may be used. natural or synthetic phospholipids or carboxymethylcellulose The compounds of the invention may also be applied in or natural or synthetic polymers in the form of powders, Solid or liquid compositions to the Soil principally to control granules or lattices, can be used in the formulations. It is those nematodes dwelling therein but also to the foliage prin 50 possible to use colorants such as inorganic pigments, for cipally to control those nematodes attacking the aerial parts of example: iron oxides, titanium oxides or Prussian Blue; the plants. The active component can be washed into the soil organic dyestuffs, such as alizarin dyestuffs, azo dyestuffs or by spraying with water or by the natural action of rainfall. metal phthalocyanine dyestuffs; or It is also possible to use During or after application, the formulation can, if desired, be trace nutrients such as salts of boron, cobalt, iron, manganese, distributed mechanically in the soil. 55 copper, cobalt, molybdenum or zinc. Application can be prior to planting, at planting, after For their agricultural application, the compounds of the planting but before sprouting has taken place or after sprout formula (I), or pesticidally acceptable salts thereof, are there ing. fore generally in the form of compositions, which are in The compounds of the invention are of particular value in various Solid or liquid forms. the protection of field, grassland, forage, plantation, glass 60 Solid forms of compositions which can be used are dusting house, orchard, grove and Vineyard crops; or of vegetables powders (with a content of the compound of formula (I), or a and salds, of ornamental plants flowers and shrubs and of pesticidally acceptable salt thereof, ranging up to 80%), wet plantation and forest trees. table powders or granules (including water dispersible gran The effective use doses of the compounds employed in the ules), particularly those obtained by extrusion, compacting, invention can vary within wide limits, particularly depending 65 impregnation of a granular carrier, or granulation starting on the nature of the pest to be eliminated or degree of infes from a powder (the content of the compound of formula (I), or tation. In general, the compositions according to the invention a pesticidally acceptable salt thereof, in these wettable pow US 7,687,533 B2 35 36 ders or granules being between about 0.5 and about 80%). Solids or inorganic salts may be dissolved in the carrier to help Solid homogenous or heterogenous compositions containing prevent settling or as antifreezes for water. one or more compounds of formula (I), or pesticidally accept The wettable powers (or powder for spraying) are usually able salts thereof, for example granules, pellets, briquettes or prepared so that they contain from about 10 to about 80% by capsules, may be used to treat standing or running water over weight of active ingredient, from about 20 to about 90% of a a period of time. A similar effect may be achieved using solid carrier, from about 0 to about 5% of a wetting agent, trickle or intermittent feeds of water dispersible concentrates from about 3 to about 10% of a dispersing agent and, when as described herein. necessary, from about 0 to about 80% of one or more stabi Liquid compositions, for example, include aqueous or non lizers and/or other additives, such as penetrating agents, adhe aqueous Solutions or Suspensions (such as emulsifiable con 10 sives, anti-caking agents, colorants, or the like. To obtain centrates, emulsions, flowables, dispersions, or solutions) or these wettable powders, the active ingredient(s) is(are) thor aerosols. Liquid compositions also include, in particular, oughly mixed in a suitable blender with additional substances emulsifiable concentrates, dispersions, emulsions, flowables, which may be impregnated on the porous filler and is(are) aerosols, wettable powders (or powder for spraying), dry ground using a mill or other Suitable grinder. This produces flowables or pastes as forms of compositions which are liquid 15 wettable powders, the wettability and the suspendability of or intended to form liquid compositions when applied, for which are advantageous. They may be suspended in water to example as aqueous sprays (including low and ultra-low Vol give any desired concentration and this suspension can be ume) or as fogs or aerosols. employed very advantageously in particular for application to Liquid compositions, for example, in the form of emulsi plant foliage. fiable or soluble concentrates most frequently comprise about The “water dispersible granules (WG)' (granules which 5 to about 80% by weight of the active ingredient, while the are readily dispersible in water) have compositions which are emulsions or Solutions which are ready for application con substantially close to that of the wettable powders. They may tain, in their case, about 0.01 to about 20% of the active be prepared by granulation of formulations described for the ingredient. Besides the solvent, the emulsifiable or soluble wettable powders, either by a wet route (contacting finely concentrates may contain, when required, about 2 to about 25 divided active ingredient with the inert filler and a little water, 50% of suitable additives, such as stabilizers, surface-active e.g. 1 to 20% by weight, or with an aqueous Solution of a agents, penetrating agents, corrosion inhibitors, colorants or dispersing agent or binder, followed by drying and screen adhesives. Emulsions of any required concentration, which ing), or by a dry route (compacting followed by grinding and are particularly suitable for application, for example, to Screening). plants, may be obtained from these concentrates by dilution 30 The rates and concentrations of the formulated composi with water. These compositions are included within the scope tions may vary according to the method of application or the of the compositions which may be employed in the present nature of the compositions or use thereof. Generally speak invention. The emulsions may be in the form of water-in-oil ing, the compositions for application to control arthropod, or oil-in-water type and they may have a thick consistency. plant nematode, helminth or protozoan pests usually contain 35 from about 0.00001% to about 95%, more particularly from The liquid compositions of this invention may, in addition about 0.0005% to about 50% by weight of one or more to normal agricultural use applications be used for example to compounds of formula (I), or pesticidally acceptable salts treat substrates or sites infested or liable to infestation by thereof, or of total active ingredients (that is to say the com arthropods (or other pests controlled by compounds of this pound of formula (I), or a pesticidally acceptable salt thereof, invention) including premises, outdoor or indoor storage or 40 together with: other Substances toxic to arthropods or plant processing areas, containers or equipment or standing or run nematodes, anthelmintics, anticoccidials, synergists, trace ning water. elements or stabilizers). The actual compositions employed All these aqueous dispersions or emulsions or spraying and their rate of application will be selected to achieve the mixtures can be applied, for example, to crops by any Suitable desired effect(s) by the farmer, livestock producer, medical or means, chiefly by spraying, at rates which are generally of the 45 Veterinary practitioner, pest control operator or other person order of about 100 to about 1,200 liters of spraying mixture skilled in the art. per hectare, but may be higher or lower (eg. low or ultra-low They are also valuable in the protection of timber (stand Volume) depending upon the need or application technique. ing, felled, converted, stored or structural) from attack by The compounds or compositions according to the invention sawflies or beetles or termites. They have applications in the are conveniently applied to vegetation and in particular to 50 protection of stored products such as grains, fruits, nuts, roots or leaves having pests to be eliminated. Another method spices and tobacco, whether whole, milled or compounded of application of the compounds or compositions according into products, from moth, beetle and mite attack. Also pro to the invention is by chemigation, that is to say, the addition tected are stored animal products such as skins, hair, wooland of a formulation containing the active ingredient to irrigation feathers in natural or converted form (e.g. as carpets or tex water. This irrigation may be sprinkler irrigation for foliar 55 tiles) from moth and beetle attack; also stored meat and fish pesticides or it can be ground irrigation or underground irri from beetle, mite and fly attack. Solid or liquid compositions gation for Soil or for systemic pesticides. for application topically to timber, Stored products or house The concentrated Suspensions, which can be applied by hold goods usually contain from about 0.00005% to about spraying, are prepared so as to produce a stable fluid product 90%, more particularly from about 0.001% to about 10%, by which does not settle (fine grinding) and usually contain from 60 weight of one or more compounds of formula (I) or pesticid about 10 to about 75% by weight of active ingredient, from ally acceptable salts thereof. about 0.5 to about 30% of surface-active agents, from about The compounds of the invention (and their pharmaceuti 0.1 to about 10% of thixotropic agents, from about 0 to about cally, veterinarily and agriculturally acceptable salts) may be 30% of Suitable additives, such as anti-foaming agents, cor used, for example, in the following applications and on the rosion inhibitors, stabilizers, penetrating agents, adhesives 65 following pests: and, as the carrier, water or an organic liquid in which the In the field of veterinary medicine or livestock husbandry active ingredient is poorly soluble or insoluble Some organic or in the maintenance of public health against arthropods US 7,687,533 B2 37 38 which are parasitic internally or externally upon vertebrates, rina); Screwworm (Cochliomyia hominivorax); Cattle particularly warm-blooded vertebrates, including man and grub (Hypoderma spp); Dermatobia hominis. domestic animals such as dogs, cats, cattle, sheep, goats, Anoplurida: Sucking lice (Menopon spp., Bovicola spp); bit equines, Swine, poultry and fish. Also, in the field of control of ing lice (Haematopinus spp., Linognathus spp., Solenoptes plant pests, soil inhabiting pests and other environmental 5 spp., Phtirus spp). pests. Illustrative of specific parasites which may be con True bugs: common bed bug (Cimicidae e.g. Cimex lectu trolled by the compounds of this invention include arthropods larius): kissing bugs (Triatoma spp e.g. Rhodnius pro Such as: lixus). Actinedida/Acaridida: chicken mite (Mesostigmata spp e.g. Brachycera: Black flies: Biting midges; Sand flies; Sciarids. Dermanyssus gallinae); itch/scab mites (Sarcoptes spp e.g. 10 Orthoptera: Periplaneta spp., Blatella spp e.g. Blatella ger Sarcoptes scabiei) mange mites (Psoroptes spp e.g. PSO manica, Gryllotalpa spp e.g. Gryllotalpa gryllotalpa, roptes ovis, Chorioptes spp e.g. Chorioptes bovis); chig Acheta domestica, Blatta Orientalis Forficula auricularia, gers (Trombicula spp e.g. Trombicula aifieddugesi); Leucophaea maderae, Melanoplus bivittatus, Melanoplus Damalinia spp.; Demodex spp., Acarapis spp., Cheyletiella femur-rubrum, Melanoplus mexicanus, Melanoplus san spp., OrnithOcheyletia spp., Myobia spp., Listrophorus spp.; 15 guinipes, Melanoplus spretus, Momadacris Septemfas Acarus spp.; Trophagus spp., Caloglyphus spp., Hypo ciata, Schistocerca peregrina, Stauronotus maroccanus, dectes spp.; Pterolichus spp., Otodectes spp., Notoedres spp.; Tachycines asynamorus. Cytodites spp., Knemidocoptes spp., Laminiosioptes spp. Dictyoptera: Periplaneta fuliginosa, Periplaneta japonica, Siphonapterida: Ctenocephalides spp e.g. Ctenocephalides Periplaneta Americana. canis, Ctenocephalides felis, Xenopsylla spp e.g. Xenop Hymenoptera: Carpenterants; Bees: Hornets; Wasps. sylla cheopis, Pulex spp e.g. Pulex irritans, Ceratophyllus Lepidoptera: Adoxophyes Orana fasciata, Agrotis ypsilon, Agrotis segetum, Alabama argillacea Hubner, Anticarsia spp. gemmatalis, Archips argyrospilla Walker; Archips rosana, TickS: Argas spp e.g. Argas persicus, Ornithodorus spp e.g. Argyresthia conjugella, Autographa gamma, Autographa Ornithodorus moubata, Otobius spp e.g. Otobius megnini; 25 nigrisigna, Barathra brassicae, Bupalus piniarius, Caco Ixodes spp e.g. Ixodes ricinus, Ixodes rubicundus, Amblyo ecia murinama, Caloptilia theivora, Capua reticulana, mma spp e.g. Amblyomma americanum, Amblyomma var Carposina niponensis, Chematobia brumata, Chilopoly iegatum, Boophilus spp e.g. Boophilus annulatus, Boophi chrysus, Chilo suppressalis Walker, Choristoneura lus decoloratus, Boophilus microplus, Dermacentor spp filmiferana, Choristoneura Occidentalis, Cirphis uni e.g. Dermacentor Silvarum, Haemophysalis spp.; 30 puncta, Cnaphalocrosis medinalis Guenee, Cydia Hyalomma spp e.g. Hyalomma truncatum, Rhipicephalus pomonella, Dendrolimus pini; Diaphania initidalis, spp e.g. Rhipicephalus sanguineus, Rhipicephalus appen Diatraea grandiosella, Earias insulana Boisduval. Earias diculatus, Rhipicephalus evertsii Dermanyssus spp.; Rail vittella Fabricius, Elasmopalpus lignosellus, Eupoecilia letia spp., Pneumonyssus spp., Stenostoma spp., Varroa spp.; and other ticks e.g. Brevipalpus phoenicis, Bryobia pra ambiguella, Evetria bouliana, Feltia subterrana, Galleria etiosa, Eotetranychus carpini, Eriophyes Sheldoni, 35 mellonella, Grapholitha finebrana, Grapholitha molesta, Paratetranychus pilosus, Phyllocoptruta oleivora, Polyph Helicoverpa armigera, Helicoverpa assulta, Helicoverpa agotarisonemus latus, Tetranychus cinnabarinus, Tetrany zea, Heliothis virescens, Hellula undalis, Hibernia defo chus kanzawai, Tetranychus pacificus, Tetranychus liaria, Hyphantria cunea, Hyponomeuta malinellus, Keif telarius. eria lycopersicella, Lambdina fiscellaria, Laphygma 40 exigua, Leucoptera coffeella, Leucoptera scitella, Lithoc Adult flies (Diptera): Horn fly (Haematobia irritans); Horse Olletis blancardella, Lobesia botrana, Loxostege Stictica fly (Tabanus spp e.g. Tabanus bovines); Stable fly (Sto lis, Lymantria monacha, Lyonetia clerkella, Malacosoma moxys calcitrans); Black fly (Simulium spp); Deer fly neustria, Mamestra brassicae, Naranga aenescens, (Chrysops spp); Louse fly (Melophagus Ovinus); Tsetse fly Notarcha derogata, Orgvia pseudotsugata, Ostrinia nubi (Glossina spp e.g. Glossina morsitans); Mosquitoes 45 lalis, Ostrinia filmacalis, Pamara guttata, Panolis flam (Culex spp e.g. Culex pipiens. Anopheles spp e.g. Anoph mea, Pectinophora gossypiella, Peridroma Saucia, Phal eles maculipennis, Aedes spp e.g. Aedes egypti, Aedes era bucephala, Phyllocnistis citrella, Pieris brassicae, vexans); Eusimulium spp., Phlebotonius spp., Lutzomyia Pieris rapae, Plutella xylostella, Pseudaletia separate; spp., Culicoides spp., Hybomitra spp., Atylotus spp., Hae Phthorimaea operculella, Phyllonorycter ringoneells, matopota spp., Philipomyia spp., Braula spp., Hydrotaea 50 Plathypena scabra, Pseudoplusia includens, Rhyacionia spp.; Morelia spp., Fannia spp e.g. Fannia Canucularis, frustrana, Scrobipalpula absoluta, Sitotroga cerealella, Calliphora spp., Wohlfahrtia spp., Sarcophaga spp., Hippo Sparganothis pilleriana, Spodoptera exigua, Spodoptera bosca spp., Lipoptena spp.; Mellophagus spp.; and other frugiperda, Spodoptera littoralis, Spodoptera litura, Diptera Such as Anastrepha ludens, Ceratitis capitata, Thaumatopoea pitvocampa, Tortrix viridans, Trichoplusia Chrysomya bezziana, Chrysomya hominivorax, Chry 55 ni Hubner; Tryporyza incertulas, Tuta absoluta, Zeira Sonya macellaria, Contarinia sorghicola, Cordylopia phera Canadensis; Lyonetid moths; Tussock moths; Case anthropophaga, Dacus cucurbitae, Dasineura brassicae, making clothes moth; Webbing clothes moth. Gasterophilus intestinalis, Haplodiplosis equestris, Hyl Coleoptera: Agrilus sinuatus, Agriotes lineatus, Agriotes emyia platura, Hypoderma lineata, Liriomyza sativae, obscurus, Amphinellus solstitialis, Anisandrus dispar, Liriomyza trifolii; Lycoria pectoralis, Mayettiola destruc 60 Anobium punctatum, Anoplophora malasiaca, Anthono tor, Musca domestica, Muscina Stabulans, Oestrus ovis, mus grandis, Anthonomus pomorum, Anthrenus verbasci, Oscinella frit, Pegomya hysocyami Phorbia brassicae, Apate monachus, Atomaria linearis, Aulacophora femora Phorbia coarctata, Rhagoletia cerasi, Rhagoletis lis, Blastophagus piniperda, Blitophaga undata, Bostry pomonella, Tipula oleraceam, Tipula paludosa; and also chos Capucins, Bruchus rufimanus, Bruchus pisorum, Blow flies; Soldierflies; Midges and Punkies. 65 Bruchis lentis, Byctiscus betulae, Callosobruchus chinen Parasitic fly maggots: Bot fly (Oestrus ovis, Cuterebra spp); sis, Cassida nebulosa, Cerotoma trifurcata, Ceuthorrhyn Blow fly (Phaenicia spp., Lucilia sericata, Lucilia cup chus assimilis, Ceuthorrhynchus napi. Chaetocnema tibi US 7,687,533 B2 39 40 alis, Chlorophorus pilosis, Conoderus vespertinus, Nematodes: Haemonchus; Ostertagia; Cooperia; Oesphagas Crioceris asparagi, Diabrotica longicomis, Dendrobium tomum; Nematodirus; Dictyocaulus; Trichuris; Dirofi pertinex, Diabrotica 12-punctata, Diabrotica virgifera, laria; AncycloStoma; Ascaris; TrichoStrongylus. Dinoderus minutes, Echinocnemus squameus, Elilachna Protozoa: Eimeria spp., Leishmania spp., Plasmodium spp.; vigintioctopunctata, Ernobius mollis, Epillachna varives Babesis spp.; Trichomonadidae spp., Toxoplasma spp and tis, Epitrix hirtipennis, Eutinobothrus brasiliensis, Het Theileria spp. erobostrychus brunneus, Hylobius abietis, Hylotrupes In the protection of Stored products, for example cereals, bajulus, Hypera brunneipennis, Hypera postica, Ips including grain or flour, groundnuts, animal feedstuffs, tim typographus, Lasioderma serricome, Lema bilineata, ber or household goods, e.g. carpets and textiles, compounds Lema melanopus, Limonius Californicus, Lissorhoptus 10 of the invention are useful against attack by arthropods such Oryzophilus, Lyctus brunneus, Lyctus linearis, Lyctus aS pubescens, Melanotus communis, Melligethes aeneus, Flour moths (Ephestia spp); Carpet beetles (Anthrenus spp); Melolontha hippocastani, Melolontha melolontha, Mint Flour beetles (Tribolium spp); Grain weevils (Sitophilus hes rugicollis, Oulema Oryzae, Ortiorrhynchus sulcatus, spp.); Mites (Acarus spp) Otiorrhynchus ovatus, Paederus fiscipes, Phaedon 15 In the protection against Soil inhabiting insects such as: cochleariae, Phyllotreta chrysocephala, Phyllophaga Western corn rootworm, other Diabrotica spp., European cha spp., Phyllopertha horticola, Phyllotreta memorum, Phyl fer and other coleopteran grubs, and wireworms; adults and lotreta striotata, Popillia japonica, Priobium carpini; larvae of the orders Hemiptera and Homoptera including Ptilinus pecticonis, Sitona lineatus, Sitophilus granaria, tarnished plant bug and other plant bugs (Miridae), aster Sphenophorus venatus, Tomicus piniperda, Tribolium cas leafhopper and other leafhoppers (Cicadellidae), rice plant taneum, Trogoxylon aequale, Xestobium rufovillosum: hopper, brown planthopper, and other planthoppers Aupreous chafer; Western cornrootworm; Rice water wee (Fulgoroidae), paylids, whiteflies (Aleurodidae), aphids vil; Adzuki bean beetle; Yellow mealworm; Red flour (Aphidae), Scales (Coccidae and Diaspididae), lace bugs beetle: Striped flea beetle: Cucurbit leaf beetle; Death (Tingidae), Stink bugs (Pentamodidae), cinch bugs and watch beetle; Drugetose beetle; Mexican bean beetle: Flea 25 other seed bugs (Lygaeidae), cicadas (Cicadidae), Spittle beetle; Japanese beetle; Boll weevil; Rice water weevil; bugs (Cercopids), squash bugs (Coreidae), red bugs and Granary weevil; Rice weevil; Wireworms (Agriotes spp.; cotton stainers (Pyrrhocoridae); adults and larvae of the Althous spp., Limonius spp); Xvleborus spp.; Tryptodendron order acari including European red mite, two spotted mite, spp., Sinoxylon spp.; rust mites, McDaniel mite and other foliar feeding mites: Homoptera: Acyrthosiphon Onobrychis, Adelges laricis, 30 adults and immatures of the order Orthoptera including Aleurodes brassicae, Aphidula masturti, Aphis fabae, grasshoppers; adults and immatures of the order Diptera Aphis gossypii, Aphis pomi, Aphis Sambuci; Aspiodotus including leafminers, midges, fruit flies (Tephritidae), and hederae, Bemisia tabaci, Bemisia argentifolii, Brachycau soil maggots; adults and immatures of the order Thysan dus cardui; Brevicoryne brassicae, Cerosipha gossypii; optera including onion thrips and other foliar feeding Cryptomyzus ribis, Diuraphis noxia, Dreyfusia nordman 35 thrips. nianae, Dreyfusia piceae, Dysaphis radicola, Dysaula For the avoidance of doubt, references herein to “treat COrthum pseudosolani, Empoasca fabae, Eriosoma lani ment' include references to curative, palliative and prophy gerum, Euscelis bilobatus, Hvalopterus arundinis, lactic treatment, references to “control’ (of parasites and/or Laodelphax Stiatellus, Lecanium comi; Macrosiphun ave pests etc.) include kill, repel, expel, incapacitate, deter, elimi nae, Macrosiphum euphorbiae, Macrosiphon rosae, 40 nate, alleviate, minimise, eradicate. Megoura viciae, Metolophium dirhodium, Myzodes persi The compounds of the invention are of particular value in cae, Myzus cerasi, Myzus persicae, Nilaparvata lugens, the control of arthropods which are injurious to, or spread or Pemphigus bursarius, Perkinsiella saccharicida, Phoro act as vectors of diseases in, man and domestic animals, for don humuli. Psylla mali. Psylla piri; Rhopalomyzus asca example those hereinbefore mentioned, and more especially lonicus, Rhopalosiphum maidis, Rhopalosiphum padi, 45 in the control of ticks, mites, lice, fleas, midges and biting, Saissetia oleae, Sappaphis mala, Sappaphis mali Schiza nuisance and myiasis flies. They are particularly useful in phis graminum, Schizoneura lanuginose, Sitobion avenae, controlling arthropods which are present inside domestic host Trialeurodes vaporariorum, Vites vitifolii. animals or which feed in or on the skin or suck the blood of the Hemiptera: Aulacorthum Solani, Aphis glycines, Eysarcoris animal, for which purpose they may be administered orally, parvus, Eurydema rugosum, Icerva purchasi, Laodelphax 50 parenterally, percutaneously or topically. striatellus, Lipaphis erysimi; Nephotettix cincticeps, Regarding the use of the compounds of the invention in Planococcus citri. Pseudococcus constocki; Riptortus mammals, there is provided: clavatus, Scotinophora lurida, Sogatella fircifera, a pharmaceutical or veterinary parasiticidal composition Stephanitis nashi. Unaspis vanomensis; Small brown plan comprising a compound of formula (I), or a pharmaceuti thopper; Brown rice planthopper; Whitebacked rice plan 55 cally or veterinarily acceptable salt thereof, or a pharma thopper; Stink bugs; Whiteflies; Lace bugs, Jumping ceutically or veterinarily acceptable solvate of either entity, plantlice. together with a pharmaceutically or veterinarily acceptable And species of the orders: Hymenoptera; Isoptera; Isopoda; diluent or carrier, which may be adapted for oral, parenteral Diplopoda; Chilopoda; Symphyla: Thysanura: Der or topical administration; 60 a compound of formula (I), or a pharmaceutically or veteri maptera; and Heteroptera: narily acceptable salt thereof, or a pharmaceutically or In the field of veterinary medicine or livestock husbandry or veterinarily acceptable solvate of either entity, or a phar in the maintenance of public health for controlling helm maceutical or veterinary composition containing any of the inths, nematodes and protozoa Such as: foregoing, for use as a medicament; Trematoda: Fasciola; Fascioloides; Paramphistomum; Dicro 65 the use of a compound of formula (I), or a pharmaceutically or coelium; Eurytrema; Ophisthorchis: Fasciolopsis: Echi veterinarily acceptable salt thereof, or a pharmaceutically nostoma; Paragonimus. or veterinarily acceptable solvate of either entity, or a phar US 7,687,533 B2 41 42 maceutical or veterinary composition containing any of the Instruments Used to Acquire Characterising Data foregoing, for the manufacture of a medicament for the Nuclear magnetic resonance spectral data were obtained treatment of a parasitic infestation; and a method of treating a parasitic infestation in a mammal using Varian Inova 300, Varian Inova 400, Varian Mercury which comprises treating said mammal with an effective 400, Varian Unityplus 400, Bruker AC 300 MHz, Bruker AM amount of a compound of formula (I), or a pharmaceuti 250 MHz or Varian T60 MHz spectrometers, the observed cally or veterinarily acceptable salt thereof, or a pharma chemical shifts being consistent with the proposed structures. ceutically or veterinarily acceptable solvate of either entity, Mass spectral data were obtained on a Waters Micromass ZQ. or a pharmaceutical or veterinary composition containing or a Hewlett Packard GCMS System Model 5971 spectrom any of the foregoing. 10 According to another aspect of the present invention, there eter. The calculated and observed ions quoted refer to the is provided a method for the control of arthropod, plant nema isotopic composition of lowest mass. HPLC means high per tode or helminth pests at a locus which comprises the treat formance liquid chromatography. Room temperature means ment of the locus (e.g. by application or administration) with 20 to 25° C. an effective amount of a compound of general formula I, or a 15 pesticidally acceptable salt thereof. Compounds of the present invention are exemplified The present invention also relates to a method of cleaning below. animals in good health comprising the application to the animal of compound of formula (I) or a veterinarily accept EXAMPLE 1. able salt. The purpose of such cleaning is to reduce or elimi nate the infestation of humans with parasites carried by the N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo animal and to improve the environment which humans rothiophenyl)-1H-pyrazol-4-yl)-N-(2,2-difluoroet inhabit. hyl)methanesulfonamide The flea membrane feed test is used to measure the bio logical activities of the compounds claimed. The assay 25 involves in vitro testing against Ctenocephalides felis con ducted according to the following general procedure. Fleas are cultured in vitro using dog blood. 25-30 adult Ctenocephalides felis (cat flea) were collected and placed in a test chamber (50 ml polystyrene tube with fine nylon mesh 30 sealing the end). Citrated dog blood was prepared by adding aqueous sodium citrate solution (10 ml, 20% w/v. 20 g sodium citrate in 100 ml water) to dog blood (250 ml). Test compounds were dissolved in dimethylsulfoxide to give a working stock Solution of 4 mg/ml. The stock Solution (12.5 35 ( \ ul) was added to citrated dog blood (5 ml) to give an initial test N1 YNH, concentration of 10 ug/ml. For testing at 30 ug/ml, working stock solutions of 12 mg/ml were prepared. C C Citrated dog blood containing the test compound (5 ml, 10 ug/ml) was placed into a plastic Petridish lid, which was kept 40 at 37° C. on a heated pad. Parafilm was stretched over the open top to form a tight membrane for the fleas to feed through. The test chamber containing the fleas was placed p1NFn:- carefully onto the parafilm membrane and the fleas com F menced feeding. 45 The fleas were allowed to feed for 2 hours and the test chambers were then removed and stored overnight at room To a mixture of N-(5-amino-3-cyano-1-2,6-dichloro-4- temperature. pentafluorothiophenyl)-1H-pyrazol-4- The fleas were observed and the percentage of fleas killed 50 yl)methanesulfonamide (200 mg, 0.42 mmol) and 2,2-dif recorded. Compounds were initially tested at 10 g/ml. luoroethyl trifluoromethanesulphonate (600 mg, 2.80 mmol) wherefrom relevant dose responses (100, 30, 10, 3, 1.0.3, 0.1 ug/ml) were conducted and repeated n=5. Data was plotted to in acetonitrile (12 ml) was added potassium carbonate (116 generate ED80, ED90 & ED95 values. mg, 0.84 mmol). The reaction mixture was then stirred at 40° The compounds of the present invention have significantly C. for 1 h. To the reaction mixture was added water (10 ml) better activity than the prior art compounds. All the examples 55 and the mixture was extracted with diethyl ether (2x8 ml). of the present invention have flea ED80 values of less than The combined extracts were dried (MgSO) and concentrated 100 ug/ml. Results for some of the compounds are presented in vacuo. The residue was dissolved in acetonitrile (1.5 ml) below. and the Solution was purified by automated preparative liquid 60 chromatography (Gilson system, 150 mmx30 mm Phenom onex LUNA II 10 um C18 column) using an acetonitrile: Example Flea feed ED80 results watergradient 50:50 to 98:2. The appropriate fractions were 5 1 concentrated in vacuo to give the titled compound (145 mg). 84 3 27 O.1 65 Experimental MH 535.9; expected 536.0. "H-NMR (DMSO): 3.05-3.09 (3H), 3.53-3.77 (1H), 3.86-4.09 (1H), 5.99-6.27 (1H), 6.53-6.61 (2H), 8.41-8.45 (2H) US 7,687,533 B2 43 EXAMPLE 2 -continued N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo rothiophenyl)-1H-pyrazol-4-yl)-1,1,1-trifluoro-N- O methylmethanesulfonamide 5 Os. - R3 R2 N n R4

10 ( \ \ )-A N1 YNH, C C N N NH2 15 C C R1a.

FN-F 2O From p1NFS Ex R1a R2 R4 R3 prep. F 9 H methylsulfonylmethyl 2 O 2-hydroxyethyl Me 10 To Preparation 14 in methanol (5 ml) was added hydro 25 1 methylthiomethyl Me 11 chloric acid (4N, 3 ml) and the reaction mixture was heated at 2 cyclopropylsulfonyl Me 17 80° C. overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate 3 N,N-dimethylsulfonyl Me 18 (20 ml) and water (20 ml). The organic layer was separated, 4 methylsulfonyl Me 12 5 H Me 15 washed with water (2x20 ml), dried (NaSO) and concen 30 trated in vacuo. The crude product was dissolved in a mixture 6 H benzyl 4 of acetonitrile, dimethyl sulphoxide and water (4:5:1, 2 ml) 7 H 2-phenylethenyl 5 and purified by automated preparative liquid chromatography 8 SFs CF methylsulfonyl Me 2O (Gilson system, 150 mmx30 mm Phenomonex LUNA C18 (2) 10um column) using an acetonitrile:Watergradient 60:40 35 to 95:5). The appropriate fractions were concentrated in 9 CF, CN () 50 vacuo to give the titled compound (60 mg). Experimental MH 539.9; expected 539.9 'H-NMR (CDC13): 3.53-3.55 (3H), 408-4.12 (2H), 7.89-7.92 (2H) Similarly prepared were: 40 EXAMPLE 3 Experimental MH 512.0; expected 512.0 "H-NMR (CDC13): 3.46-3.46 (2H), 6.28-6.31 (1H), 7.32-7.38 (1H), 45 7.56-7.61 (2H), 7.77-7.79 (2H)

EXAMPLE 4

50 N NH2 Experimental MH 468.2: expected 468.0 'H-NMR (CDC13): 0.17-0.23 (2H), 0.50-0.56 (2H), 0.97-1.05 (1H), 3.06-3.07 (3H), 3.50-3.55 (2H), 4.15-4.19 (2H), 7.77-7.78 (2H) 55 EXAMPLE 5 R1a. Experimental MH" 453.2; expected 453.0 H-NMR From (CDC13): 3.08-3.12 (3H), 3.30-3.39 (2H), 4.49-4.52 (2H), Ex R1a R2 R4 R3 prep. 60 7.69-7.72 (2H) CF CN H 3,4-difluorophenyl cyclopropylmethyl cyanomethyl EXAMPLE 6 pyridin-2-ylmethyl e benzyl 2-(N.N- 65 Experimental MH 505.3; expected 505.0 'H-NMR dimethylamino)ethyl (CDC13): 3.06-3.08 (3H), 4.91-4.98 (2H), 7.23-728 (2H), 7.32-7.36 (1H), 7.71-7.73 (2H), 8.51-8.54 (1H) US 7,687,533 B2 45 46 EXAMPLE 7 EXAMPLE 1.8 Experimental MH 504.3; expected 504.0 'H-NMR Experimental MH 592.9; expected 592.9 'H-NMR (CDC13): 3.15-3.16 (3H), 3.66-3.71 (2H), 7.24-728 (3H), (CDC13): 3.38-3.42 (6H), 406-4.12 (2H), 7.89-7.92 (2H) 7.29-7.33 (2H), 7.67-7.69 (2H)

EXAMPLE 8 EXAMPLE19

Experimental MH" 485.0; expected 485.1 H-NMR 10 Experimental MH 440.0; expected 440.0 'H-NMR (CDC13): 2.19-2.38 (6H), 2.41-2.57 (2H), 3.10-3.15 (3H), (CDC13): 2.54-2.67 (2H), 3.33-3.44 (2H), 3.79-3.89 (2H), 3.70-3.94 (2H), 4.97-5.23 (2H), 7.75-7.78 (2H) 420-4.36 (2H), 7.73-7.81 (2H) EXAMPLE 9 15 EXAMPLE 20 Experimental MH" 491.9; expected 492.0 'H-NMR (DMSO): 3.19-3.22 (3H), 4.98-5.03 (2H), 6.19-6.28 (2H), N-5-amino-3-cyano-1-(2,6-dichloro-4-(trifluorom 8.19-8.25 (2H), 9.83-9.87 (1H) ethyl)phenyl)-1H-pyrazol-4-yl)-1,1,1-trifluoro-N- methylmethanesulfonamide EXAMPLE 10 Experimental MH" 458.0; expected 458.0 'H-NMR (CD3OD): 3.07-3.08 (3H), 3.61-3.75 (4H), 7.98-8.01 (2H) 25 EXAMPLE 11 'H-NMR (CDC13): 2.23-2.25 (3H), 3.10-3.12 (3H), 4.21 4.25 (2H), 4.76-4.80 (2H), 7.77-7.78 (2H) 30

EXAMPLE 12 Experimental MH 517.9; expected 518.0 'H-NMR (CD3OD): 118-1.26 (4H), 3.06-3.10 (1H), 3.45-3.46 (3H), 35 C 7.55-7.59 (2H)

EXAMPLE 13 Experimental MH 520.9; expected 521.0 'H-NMR 40 (CDC13): 2.98-3.02 (6H), 3.44-3.47 (3H), 4.25-4.33 (2H), 7.76-7.80 (2H) EXAMPLE 1.4 45 To a solution of N-(3-cyano-1-2,6-dichloro-4-(trifluo romethyl)phenyl-5-(dimethylamino)methylenelamino Experimental MH" 491.9; expected 492.0 'H-NMR 1H-pyrazol-4-yl)-1,1,1-trifluoro-N-methylmethanesulfona (CDC13): 3.44-3.54 (6H), 4.11-4.23 (2H), 7.75-7.85 (2H) mide (240 mg, 0.45 mmol) in methanol (7 ml) was added 50 EXAMPLE 1.5 hydrochloric acid (4N, 4 ml) and the reaction mixture was heated at reflux for 4 h. The reaction mixture was concen Experimental MH 414.0; expected 414.0. 'H-NMR trated under nitrogen and the residue partitioned between (CD3OD): 3.02-3.07 (3H), 7.97-8.02 (2H) ethyl acetate and water. The two layers were separated and the 55 aqueous layer was extracted with ethyl acetate (x2). The EXAMPLE 16 combined organic phases were dried (MgSO4) and concen trated under nitrogen. The crude product was dissolved in Experimental MH 490.0; expected 490.0 'H-NMR acetonitrile (4 ml) and purified by automated preparative (CD3OD): 4.41-444 (2H), 7.30-7.37 (3H), 7.41-7.46 (2H), 60 liquid chromatography (Gilson system, 150 mmx21.2 mm 7.95-8.01 (2H) Phenomonex LUNA 100 A C18 column) using an acetoni EXAMPLE 17 trile:water gradient 50:50 to 98:2). The appropriate fractions were concentrated in vacuo to give the titled compound (105 mg). Experimental MH 502.0; expected 502.0 'H-NMR 65 (CD3OD): 6.97-703 (1H), 7.25-7.31 (1H), 7.35-7.40 (3H), Experimental MH" 482.0; expected 482.0 "H-NMR 7.52-7.56 (2H), 7.90-7.95 (2H) (CDC13): 3.50-3.52 (3H), 4.00-4.10 (2H), 7.71-7.76 (2H) US 7,687,533 B2 47 48 EXAMPLE 21 EXAMPLE 22 N-5-amino-3-cyano-1-2,6-dichloro-4-(trifluorom N-5-amino-3-cyano-1-(2,6-dichloro-4-(trifluorom ethyl)phenyl)-1H-pyrazol-4-yl)-N-(cyclopropylm ethyl)phenyl)-1H-pyrazol-4-yl)-N-(2,2,2-trifluoroet ethyl)-1,1,1-trifluoromethanesulfonamide hyl)methanesulfonamide

10

15 F F N F O \ N /N HC O C ( \ N1 YNH, C C 25

30 To a solution of N-(3-cyano-1-2,6-dichloro-4-(trifluo romethyl)phenyl-5-(dimethylamino)methylenelamino 1H-pyrazol-4-yl)-1,1,1-trifluoromethanesulfonamide (250 To a solution of N-(3-cyano-1-2,6-dichloro-4-(trifluo mg, 0.48 mmol) in acetone (6 ml) was added potassium 35 romethyl)phenyl-5-(dimethylamino)methylenelamino carbonate (100mg 0.72 mmol), a catalytic amount of sodium 1H-pyrazol-4-yl)methanesulfonamide (250 mg 0.53 mmol) iodide and (bromomethyl)cyclopropane (69.5 ul, 0.72 in 1-methyl-2-pyrrolidinone (anhydrous, 5 ml) was added sodium hydride (60% in oil, 16.6 mg, 0.69 mmol) and 2.2.2- mmol). The reaction mixture was then stirred at 60°C. over 40 night. The reaction mixture was concentrated under a stream trifluoroethyl trichloromethanesulphonate (195 mg 0.69 of nitrogen and the residue was partitioned between dichlo mmol). The reaction mixture was then stirred at room tem romethane (20 ml) and water (20 ml). The two layers were perature for 3 h. To the reaction mixture was added dichlo separated and the organic phase was washed with water, dried 45 romethane (20 ml) and the resulting mixture was extracted (NaSO4) and concentrated in vacuo to give the protected with water (20 ml). The organic phase was washed with water compound. To a solution of the protected compound in (2x20 ml) and brine (2x20 ml), dried (NaSO) and concen methanol (5 ml) was added hydrochloric acid (4M, 3 ml) and trated in vacuo. To the residue was added methanol (5 ml) and the reaction mixture was heated at reflux. The reaction mix 50 hydrochloric acid (4M, 3 ml) and the mixture was heated at ture was concentrated in vacuo and the residue was extracted reflux for 60 h. The reaction mixture was concentrated in with ethyl acetate (20 ml). The organic phase was washed vacuo and to the residue was added ethyl acetate (20 ml) and with water (2x20 ml), dried (NaSO) and concentrated in water (20 ml). The organic phase was separated, washed with vacuo. The crude product was dissolved in a mixture of aceto 55 water (2x20 ml) and brine (2x20 ml), dried (Na2SO) and nitrile (1 ml), dimethylsulphoxide (2.4 ml) and water (0.6 ml) concentrated in vacuo. The crude product was dissolved in and purified by automated preparative liquid chromatography acetonitrile/dimethyl sulphoxide/water (1:4:1, 6 ml) and (Gilson system, 150 mmx30 mm Phenomonex LUNA C18 purified by automated preparative liquid chromatography (2) 10um column) using an acetonitrile:Watergradient 60:40 60 (Gilson system, 150 mmx30 mm Phenomonex LUNA C18 to 95:5). The appropriate fractions were concentrated in (2) 10 um column) using an acetonitrile:Water gradient 52.5: vacuo to give the titled compound (120 mg). 47.5 to 95:5). The appropriate fractions were concentrated in Experimental MH 522.3; expected 522.0 'H-NMR vacuo to give the titled compound (135 mg). 65 (CDC13): 0.19-0.29 (2H), 0.54-0.64 (2H), 0.99-1.10 (1H), Experimental MH" 496.2: expected 496.0 'H-NMR 3.53-3.78 (2H), 4.01-413 (2H), 7.72-7.84 (2H) (CDC13): 3.10-3.14 (3H), 4.07-4.33 (4H), 7.74-7.80 (2H) US 7,687,533 B2 49 50 EXAMPLE 23 To a solution of N-(5-amino-3-cyano-1-2,6-dichloro-4- (trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-N-(methylthio) N-5-amino-3-cyano-1-2,6-dichloro-4-(trifluorom methylmethanesulfonamide (108 mg 0.23 mmol) in acetone ethyl)phenyl)-1H-pyrazol-4-yl)-1,1,1-trifluoro-N- (35 ml) was added sodium carbonate (318 mg, 3.04 mmol), (methylsulfonyl)methanesulfonamide followed by OxoneR (924 mg, 1.52 mmol) in water (12 ml). The reaction mixture was then stirred at room temperature for 5h. To the reaction mixture was added water and the solution was extracted with ethyl acetate. The combined extracts were 10 washed with brine, dried (MgSO) and concentrated in vacuo. The crude product was dissolved in a mixture of acetonitrile (1 ml) and water (1 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mmx30mm Phe nomenex LUNAC18(2) 10um column) using an acetonitrile: 15 watergradient 45:55 to 95:5). The appropriate fractions were C concentrated in vacuo to give the titled compound (55 mg). Experimental MH 505.9; expected 506.0 'H-NMR (CDC13): 3.05-3.07 (3H), 3.15-3.18 (3H), 4.43-4.54 (2H), 7.74-7.80 (2H)

EXAMPLE 25 N-5-amino-3-cyano-1-(2,6-dichloro-4-(trifluorom To a solution of N-(5-amino-3-cyano-1-2,6-dichloro-4- 25 (trifluoromethyl)phenyl)-1H-pyrazol-4- ethyl)phenyl)-1H-pyrazol-4-yl)-N-cyclobutyl-1,1,1- yl)methanesulfonamide (73 mg, 0.18 mmol) in dichlo trifluoromethanesulfonamide romethane (4 ml), at 0°C., was added dropwise triethylamine (30 ul, 0.21 mmol), followed by trifluoromethanesulphonic anhydride (30 ul, 0.18 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 h. To 30 the reaction mixture was added water and dichloromethane. The two layers were separated and the aqueous layer was extracted with dichloromethane (x3). The combined organic phases were then dried (MgSO4) and concentrated in vacuo. The crude product was dissolved in acetonitrile/water (7:3, 5 35 ml) and purified by automated preparative liquid chromatog raphy (Gilson system, 150 mmx30 mm Phenomenex LUNA C18(2) 10 um column) using an acetonitrile:Water gradient 55:45 to 95:5). The appropriate fractions were concentrated C in vacuo to give the titled compound (50 mg). Experimental MH 543.9; expected 543.9 'H-NMR 40 (CDC13): 3.57-3.58 (3H), 4.12-4.20 (2H), 7.77-7.81 (2H) EXAMPLE 24 N-5-amino-3-cyano-1-2,6-dichloro-4-(trifluorom 45 ethyl)phenyl)-1H-pyrazol-4-yl)-N-(methylsulfonyl) methylmethanesulfonamide To a solution of Preparation 12 (250 mg, 0.43 mmol) in CH tetrahydrofuran (15 ml) was added hydrochloric acid (4M, 15 s( 50 ml). The reaction mixture was then heated at reflux overnight. so The reaction mixture was concentrated in vacuo and the resi \ O due was partitioned between water (50 ml) and dichlo N Nn M romethane (75 ml). The organic layer was separated, dried 7Nch 55 (Na2SO4) and concentrated in vacuo. The crude product was N \ { ". dissolved in acetonitrile (6 ml) and the solution was passed N1 YNH, through a 0.45u filter. The solution was then purified by C C automated preparative liquid chromatography (Gilson sys 60 tem, 150 mmx30 mm Phenomonex LUNA II 10u C18 col umn) using an acetonitrile:water gradient 60:40 to 95:5). The appropriate fractions were concentrated in vacuo to give the F F titled compound (113 mg). 65 Experimental MH 522.0; expected 522.0 'H-NMR (Ac etone): 0.23-0.31 (2H), 0.56-0.64 (2H), 1.12-1.20 (1H), 3.56 3.78 (2H), 6.12-6.22 (2H), 8.02-8.13 (2H) US 7,687,533 B2 51 52 EXAMPLE 26 To a solution of Example 20 (150 mg. 0.31 mmol) in N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo tetrahydrofuran (5 ml) was added dropwise tert-butyl nitrite rothiophenyl)-1H-pyrazol-4-yl)-N-(methylsulfonyl) (111 ul, 0.93 mmol). The reaction mixture was then heated at methanesulfonamide 60° C. overnight. The reaction mixture was concentrated in HiQ O vacuo and the residue was partitioned between ethyl acetate N S 2 O (20 ml) and water (20 ml). The organic layer was separated, \ 21\N-S-CH || washed with brine (20 ml), dried (Na2SO) and concentrated 10 in vacuo. The residue was purified by column chromatogra ( \ phy (silica, 10 g) eluting with dichloromethane/ethyl acetate N1 YNH, 9:1. The appropriate fractions were combined and concen

C C 15 trated to give the crude product. The crude product was dis solved in a mixture of acetonitrile, dimethyl sulphoxide and water (4:5:1, 2 ml) and purified by automated preparative n liquid chromatography (Gilson system, 150 mmx30mm Phe 1 NF nomonex LUNAC18(2) 10um column) using an acetonitrile: F watergradient 60:40 to 95:5). The appropriate fractions were concentrated in vacuo to give the titled compound (80 mg). To a solution of Preparation 23 (200 mg. 0.45 mmol) in anhydrous dichloromethane (5 ml), at 0°C., was added tri Experimental MH 467.0; expected 467.0 'H-NMR ethylamine (124 ul, 0.9 mmol) and methanesulphonyl chlo 25 (CDC13): 3.65-3.65 (3H), 7.77-7.80 (2H), 7.80-7.82 (1H) ride (70 ul, 0.9 mol). The reaction mixture was then stirred under nitrogen for 30 min. To the reaction mixture was added Similarly prepared was: dichloromethane (20 ml) and the resulting mixture was extracted with water (20 ml). The organic phase was washed with water (2x20 ml) and brine (2x20 ml), dried (NaSO) 30 EXAMPLE 28 and concentrated in vacuo. To the residue was added metha nol (5 ml) and hydrochloric acid (4M, 3 ml) and the mixture was heated at reflux for 60 h. The reaction mixture was N-3-cyano-1-(2,6-dichloro-4-(trifluoromethyl)phe concentrated in vacuo and to the residue was added ethyl nyl)-1H-pyrazol-4-yl)-N-(methylsulfonyl)methane acetate (20 ml) and water (20 ml). The organic phase was 35 Sulfonamide separated, washed with water (2x20 ml) and brine (2x20 ml), dried (NaSO) and concentrated in vacuo. The crude product was dissolved in a mixture of acetonitrile and water (1:1:5ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mmx30 mm Phenomonex LUNA C18 (2) 10um column) using an acetonitrile:Watergradient 60:40 40 to 95:5). The appropriate fractions were concentrated in vacuo to give the titled compound (80 mg). Experimental MH 549.9; expected 549.9 'H-NMR HiQ O (CDC13): 3.41-3.47 (6H), 4.09-4.19 (2H), 7.88-7.94 (2H) N S 2 O 45 \ o?\ || N-S-CH EXAMPLE 27 | N-3-cyano-1-(2,6-dichloro-4-(trifluoromethyl)phe \ O NS nyl)-1H-pyrazol-4-yl)-1,1,1-trifluoro-N-methyl 50 N methanesulfonamide C C N HC O F \ \N 4.v ( F 55

F F F C C 60

from the compound of Example 14 (1.00 g, 2.03 mmol) to give the title compound (855 mg). 65 Experimental MH" 477.0; expected 477.0 'H-NMR (CDC13): 3.45-3.46 (6H), 7.75-7.78 (2H), 7.80-7.83 (1H) US 7,687,533 B2 53 54 EXAMPLE 29 To a solution of Example 28 (855 mg, 1.79 mmol) in tetrahydrofuran (20 ml) was added potassium carbonate (617 N-3-cyano-1-2,6-dichloro-4-pentafluorothiophe mg, 4.48 mmol) in methanol (20 ml), containing a few drops nyl)-1H-pyrazol-4-yl)-N-(methylsulfonyl)methane of water. The reaction mixture was then stirred at room tem Sulfonamide perature for 2 h. The reaction mixture was concentrated in vacuo and to the residue was added hydrochloric acid (2M, 50 ml) and dichloromethane (100 ml). The organic phase was then separated, dried (Na2SO4) and concentrated in vacuo. 10 HiQ 2 O O The residue was purified using an IsoluteTM cartridge (silica, N\ o?\S || 20 g) with gradient elution, cyclohexane:ethyl acetate 1:0 to N-S-CH 1:1. The appropriate fractions were combined and concen trated to give the titled compound (600mg). 15 Experimental MH 399.0; expected 399.0 'H-NMR (CDC13): 3.08-3.10 (3H), 6.69-6.74 (1H), 7.73-7.78 (2H), C C 7.80-7.84 (1H)

EXAMPLE 31 N-3-cyano-1-(2,6-dichloro-4-(trifluoromethyl)phe 25 nyl)-1H-pyrazol-4-yl)-N-(2,2,2-trifluoroethyl)meth anesulfonamide To a solution of Example 26 (310 mg. 0.56 mmol) in tetrahydrofuran (4 ml) was added dropwise tert-butyl nitrite (200 ul, 1.69 mmol). The reaction mixture was then heated at reflux for 16 h. The reaction mixture was concentrated in 30 vacuo and the crude product was dissolved in acetonitrile (6 ml). The solution was passed through a 0.45u filter and puri F fied by automated preparative liquid chromatography (Gilson F system, 150 mmx30 mm Phenomonex LUNA II 10u C18 35 N F column) using an acetonitrile: water gradient 60:40 to 95:5). \ , , The appropriate fractions were concentrated in vacuo to give N4. the titled compound (169 mg). MNCH H-NMR (Acetone): 3.56-3.57 (6H), 8.28-8.35 (2H), 8.73 Nf \ / 3 8.79 (1H) 40 YN C C EXAMPLE 30

N-3-cyano-1-(2,6-dichloro-4-(trifluoromethyl)phe 45 nyl)-1H-pyrazol-4-yl)methanesulfonamide F F F

50 N \ S--ch, To a solution of sodium hydride (60% in oil, 14 mg. 0.35 O mmol) in 1-methyl-2-pyrrolidinone (6 ml) was added ( ) 55 Example 30 (115 mg, 0.29 mmol), followed by 2.2.2-trifluo N roethyl trichloromethane sulphonate (185 mg, 0.66 mmol), C C added via Syringe. The reaction mixture was then heated at 65° C. for 6 days. The reaction mixture was concentrated in 60 vacuo and the residue was purified using an IsoluteTM car tridge (silica, 5 g) with gradient elution, dichloromethane: methanol 100:0 to 95:5). The appropriate fractions were F F F combined and concentrated to give the titled compound (41 65 mg). H-NMR (CDC13): 3.09-3.13 (3H), 4.27-4.34 (2H), 7.72 7.79 (2H), 7.83-7.87 (1H) US 7,687,533 B2 55 EXAMPLE 32 -continued N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo rothiophenyl)-1H-pyrazol-4-yl)-N-(2.2.2-trifluoroet O hyl)methanesulfonamide Os. - Me R2 N YR4 10 ( \ N1 YNH, C C

15

R1a. C Ex R1a. R2 R4 From Prep

35 OCF CN 21 36 SFs COCH 38 25 37 OCHF, CN 22

To a solution of Preparation 24 (80 mg, 0.13 mmol) in dioxane (2 ml) and methanol (1 ml) was added hydrochloric acid (5N, 1 ml). The reaction mixture was then heated at 85° 30 EXAMPLE 33 C. overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between water (5 ml) and Experimental MH 567.0; expected 567.0 'H-NMR ethyl acetate (10 ml). The organic layer was separated, dried (CDC13): 2.97-3.02 (3H), 405-4.18 (2H), 4.34-4.42 (2H), (MgSO4) and concentrated in vacuo. The crude product was 35 4.69-4.96 (2H), 7.88-7.91 (2H), 7.91-7.95 (1H), 8.34-8.39 dissolved in a mixture of acetonitrile and water and dimethyl (1:2, 1.6 ml) and purified by automated preparative liquid (1H) chromatography (Gilson system, 150 mmx30 mm Phenom onex LUNA C18(2) 10 um column) using an acetonitrile: water gradient 55:45 to 95:5). The appropriate fractions were 40 EXAMPLE 34 concentrated in vacuo to give the titled compound (43 mg). Experimental MH" 553.9; expected 554.0 'H-NMR Experimental MH 567.9; expected 567.9 H-NMR (CDC13): 3.11-3.14 (3H), 4.12-4.30 (4H), 7.90-7.93 (2H) (CDC13): 3.43-3.47 (6H), 4.09-420 (2H), 5.36-5.44 (1H), Similarly prepared were: 45 6.58-6.65 (1H), 7.89-7.93 (2H)

O EXAMPLE 35

Os, -Me 50 Experimental MH 507.9; expected 508.0 'H-NMR R2 N n R4 (CDC13): 3.43-3.46 (6H), 408-4.12 (2H), 7.39-7.41 (2H)

( \ EXAMPLE 36 N1 YNH, 55 C C Experimental MH 566.9; expected 566.9 'H-NMR (CDC13): 2.91-2.94 (3H), 3.10-3.13 (3H), 4.23-4.32 (2H), 60 4.62-4.66 (2H), 6.65-6.69 (1H), 7.91-7.93 (2H)

R1a. EXAMPLE 37 Ex R1a. R2 R4 From Prep Experimental MH" 489.9; expected 490.0 'H-NMR 33 SFs CN 2-(1H-1,2,4-triazoly-yl)ethyl 42 65 34 CONH, Methylsulfonyl 37 (CDC13): 3.43-3.46 (6H), 4.09-4.13 (2H), 6.56-6.65 (1H), 7.30-7.32 (2H) US 7,687,533 B2 57 58 EXAMPLE 38 To a solution of Preparation 25 (155 mg, 0.24 mmol) in dioxane (3 ml) and methanol (1 ml) was added hydrochloric N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo acid (5N, 0.5 ml). The reaction mixture was then heated at 90° rothiophenyl)-1H-pyrazol-4-yl)methanesulfonamide C. for 5 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (6 ml) and water (6 ml). The organic phase was separated, dried N Osy CH3 (MgSO4) and concentrated in vacuo. The crude product was dissolved in acetonitrile/dimethyl sulphoxide (1:1, 1.2 ml) and the Solution was purified by automated preparative liquid 10 chromatography (Gilson system, 150 mmx30 mm Phenom onex LUNA II 10 um C18 column) using an acetonitrile: N NH2 watergradient 60:40 to 95:5). The appropriate fractions were concentrated in vacuo to give the titled compound (72 mg). C C 15 Experimental MH 593.9; expected 594.0 'H-NMR (CDC13): 0.61-0.87 (2H), 0.99-1.06 (2H), 3.00-3.04 (3H), 3.44-3.64 (1H), 4.14-4.38 (3H), 7.89-7.93 (2H) p1NFni EXAMPLE 40 F N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo rothiophenyl)-1H-pyrazol-4-yl)-N-(methylsulfonyl) To a solution of Preparation 3 (121 mg, 0.23 mmol) in ethanesulfonamide dioxane (4 ml) and methanol (1 ml) was added hydrochloric 25 acid (5N, 0.5 ml). The reaction mixture was then heated at 90° C. for 5 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (5 ml) and water (5 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2x5ml). The 30 combined organic phases were dried (MgSO4) and concen O CH trated in vacuo. The crude product was dissolved in acetoni N sy trile/dimethyl sulphoxide (1:1, 0.15 ml) and the solution was purified by automated preparative liquid chromatography \ (Gilson system, 150 mmx30 mm Phenomonex LUNA II 10 35 (Sch, um C18 column) using an acetonitrile:water gradient 50:50 N \ ^\, to 95:5). The appropriate fractions were concentrated in N1 YNH, vacuo to give the titled compound (63 mg). Experimental MH" 471.8; expected 472.0 'H-NMR C C (CDC13): 3.10-3.13 (3H), 4.25-4.31 (2H), 5.98-6.01 (1H), 40 7.89-7.92 (2H) n 1F EXAMPLE 39 F1 NF N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo 45 F rothiophenyl)-1H-pyrazol-4-yl)-N-1-(trifluorom ethyl)cyclopropyl)methylmethanesulfonamide To a mixture of Example 38 (200 mg, 0.42 mmol) and ethanesulphonyl chloride (0.11 ml, 1.20 mmol) in acetonitrile CH 50 (12 ml) was added potassium carbonate (116 mg, 0.84 mmol). The reaction mixture was then stirred at room temperature for N o==o 66 h. The reaction mixture was concentrated in vacuo and the F residue was partitioned between water (20 ml) and ethyl 55 acetate (20 ml). The two layers were separated and the N1 YNH, organic layer was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in acetonitrile/water (9:1, 4 ml) C C and the Solution was purified by automated preparative liquid 60 chromatography (Gilson system, 150 mmx30 mm Phenom onex LUNA II 10 um C18 column) using an acetonitrile: watergradient 55:45 to 95:5). The appropriate fractions were p1NF'n' concentrated in vacuo to give the titled compound (143 mg). F 65 Experimental MH 563.9; expected 563.9 'H-NMR (DMSO): 1.31-137 (3H), 3.45-3.49 (3H), 3.53-3.68 (2H), 6.74-6.81 (2H), 8.40-8.44 (2H) US 7,687,533 B2 59 60 EXAMPLE 41 The organic layer was washed with water, dried (MgSO) and concentrated in vacuo. The residue was dissolved in acetoni methyl 5-amino-3-cyano-1-2,6-dichloro-4-(trifluo trile/water (9:1, 8 ml) and the solution was purified by auto romethyl)phenyl)-1H-pyrazol-4-yl(methylsulfonyl) mated preparative liquid chromatography (Gilson system, carbamate 150 mmx30mm Phenomonex LUNA II 10 um C18 column) using an acetonitrile:water gradient 50:50 to 95:5). The appropriate fractions were concentrated in vacuo to give the titled compound (54 mg). HC V Experimental MH" 485.8: expected 486.0 'H-NMR O 10 (DMSO): 299-3.03 (3H), 3.14-3.17 (3H), 6.40-6.46 (2H), 8.41-8.44 (2H) N, O= Similarly prepared from Example 38 were: \ N-S-CH

15 i? \ . O N1 YNH, Os Me

C C NC N n R4 ( \ N1 YNH, F F C C F 25

To a solution of Example 15 (100 mg, 0.24 mmol) in acetone (4 ml) was added potassium carbonate (50 mg, 0.36 mmol) and methyl chloroformate (22.4 ul, 0.29 mmol). The SFs reaction mixture was then heated at reflux for 3 h. The reac 30 tion mixture was concentrated in vacuo and the residue was Ex R4 partitioned between dichloromethane and water. The two lay 43 2-fluororoethyl ers were separated and the aqueous layer was extracted with 44 1,2,4-oxadiazol-3-ylmethyl dichloromethane (x3). The combined organic layers were 45 aminocarbonylmethyl 35 46 1H-pyrazol-3-ylmethyl then dried (MgSO) and concentrated in vacuo. The crude 47 2,2,3,3,3-pentafluoropropyl product was dissolved in acetonitrile/water (4:1, 5 ml) and 48 2-pyrrollidin-1-ylethyl purified by automated preparative liquid chromatography 49 2-morpholin-4-ylethyl (Gilson system, 150 mmx30mm Phenomenex LUNAC18(2) 10 um column) using an acetonitrile:water gradient 50:50 to 95:5). The appropriate fractions were concentrated in vacuo 40 EXAMPLE 43 to give the titled compound (90 mg). Experimental MH 471.8; expected 472.0 'H-NMR Experimental MH 517.9; expected 518.0 'H-NMR (CD3OD): 3.50-3.52 (3H), 3.85-3.86 (3H), 7.96-8.00 (2H) (DMSO): 3.01-3.06 (3H), 3.61-3.93 (2H), 4.38-444 (1H), 45 4.50-4.56 (1H), 6.44-6.51 (2H), 8.41-8.44 (2H) EXAMPLE 42 EXAMPLE 44 N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo rothiophenyl)-1H-pyrazol-4-yl)-N-methylmethane Experimental MH 553.9; expected 554.0 'H-NMR Sulfonamide (DMSO): 3.12-3.14 (3H), 4.69-5.03 (2H), 6.54-6.59 (2H), 50 8.40-8.43 (2H), 9.61-9.63 (1H) EXAMPLE 45 CH CH N 3 CH 3 Experimental MH 528.9; expected 529.0 'H-NMR F Na / 55 (DMSO): 2.28-2.31 (3H), 3.46-3.57 (2H), 4.00-4.01 (2H), FY-S N s 7s// no 7.36-7.38 (2H) F1 F N2-NOS EXAMPLE 46 C n 60 Experimental MH 552.0; expected 552.0 "H-NMR (CDC13): 3.15-3.20 (3H), 490-4.97 (2H), 5.43-5.57 (2H), To a mixture of Example 38 (200 mg, 0.42 mmol) and 6.40-6.43 (1H), 7.61-7.65 (1H), 7.87-7.90 (2H) methyl iodide (52 ul, 0.84 mmol) in acetonitrile (12 ml) was added potassium carbonate (116 mg. 0.84 mmol). The reac EXAMPLE 47 tion mixture was then stirred at room temperature for 66 h. 65 The reaction mixture was partitioned between hydrochloric Experimental MH 603.9; expected 604.0 'H-NMR acid (1M) and ethyl acetate and the two layers were separated. (CDC13): 3.10-3.14 (3H), 4.20-4.27 (2H), 7.90-7.93 (2H) US 7,687,533 B2 61 62 EXAMPLE 48 EXAMPLE 51 N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo Experimental MH" 569.0; expected 569.0 'H-NMR rothiophenyl)-1H-pyrazol-4-yl)-N-(5-methylisox (CDC13): 1.67-1.83 (4H), 2.41-2.76 (6H), 3.08-3.15 (3H), azol-3-yl)methylmethanesulfonamide 3.51-3.99 (2H), 5.02-5.30 (2H), 7.88-7.91 (2H)

O CH EXAMPLE 49 10 Experimental MH 585.0; expected 585.0 'H-NMR (CDC13): 2.41-2.55 (4H), 2.56-2.59 (4H), 3.09-3.14 (3H), 3.61-3.73 (4H), 4.72-4.91 (2H), 7.88-7.91 (2H) 15 EXAMPLE SO C N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo rothiophenyl)-1H-pyrazol-4-yl)-N-(1-methyl-1H imidazol-2-yl)methylmethanesulfonamide

25 To a mixture of Example 38 (200 mg, 0.42 mmol) and 3-chloromethyl-5-methylisoxazole (84 mg. 0.64 mmol) in acetonitrile (12 ml) was added potassium carbonate (116 mg, 0.84 mmol). The reaction mixture was then stirred at 40°C. for 18 h. To the reaction mixture was added water (6 ml) and 30 ethyl acetate (10 ml). The two layers were separated and the V aqueous layer was extracted with ethyl acetate (2x5ml). The f \ CH combined organic phases were dried (MgSO) and concen N trated in vacuo to give a mixture of products. The residue was N1 YNH, dissolved in acetonitrile/water (3.1 ml) and the solution was 35 purified by automated preparative liquid chromatography C C (Gilson system, 150x50 mm, LUNA II C1810 um column) using an acetonitrile:water gradient 50:50 to 95:5). The appropriate fractions were concentrated to give the titled compound (144 mg). ni 40 Experimental MH 566.9; expected 567.0 'H-NMR p1NF (CDC13): 2.35-2.39 (3H), 3.11-3.15 (3H), 4.41-449 (2H), F 4.81-4.87 (2H), 6.01-6.04 (1H), 7.86-7.89 (2H) EXAMPLE 52 To a mixture of Example 38 (200 mg, 0.42 mmol) and 45 {5-amino-3-cyano-1-(2,6-dichloro-4-pentafluo 1-(N-methyl)-2-chloromethylimidazole (106 mg, 0.64 rothiophenyl)-1H-pyrazol-4-yl(methylsulfonyl) mmol) in acetonitrile (12 ml) was added potassium carbonate aminomethyl pivalate (116 mg, 0.84 mmol). The reaction mixture was then stirred at 40° C. for 18 h. To the reaction mixture was added water (6 50 ml) and ethyl acetate (10 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2x5 ml). The combined organic phases were then dried (MgSO) CH and concentrated in vacuo. The residue was dissolved in 55 CH acetonitrile/water (3 ml) and the solution was purified by \ CH automated preparative liquid chromatography (Gilson sys tem, 150x50 mm, LUNA II C18 10 um column) using an C acetonitrile: water gradient 45:55 to 95:5). The appropriate 60 fractions were concentrated to give the titled compound (98 mg). Experimental MH" 565.9; expected 566.0 'H-NMR (CDC13): 2.88–2.91 (3H), 3.70-3.74 (3H), 4.80-5.03 (2H), 65 6.09-6.18 (2H), 6.87-6.89 (1H), 6.92-6.95 (1H), 7.87-7.90 (2H) US 7,687,533 B2 63 64 To a solution of Example 26 (200 mg, 0.36 mmol) and To a mixture of Example 38 (200 mg, 0.42 mmol), potas potassium carbonate (150 mg, 1.08 mmol) in acetonitrile (5 sium carbonate (116 mg. 0.84 mmol) and potassium iodide ml) was added chloromethyl pivalate (0.16 ml, 1.08 mmol) and potassium iodide (10 mg). The reaction mixture was then (140 mg. 0.84 mmol) in acetonitrile (12 ml) was added benzyl heated at 50° C. for 16 h. The reaction mixture was passed bromide (100 ul, 0.84 mmol). The reaction mixture was then through a silica plug, eluting with methanol/dichloromethane stirred at room temperature for 16h. The reaction mixture was 5:95. The filtrate was then concentrated in vacuo. The resi partitioned between hydrochloric acid (2M) and dichlo due was dissolved in acetonitrile (1.5 ml) and purified by romethane and the two layers were separated. The organic automated preparative liquid chromatography (Gilson sys layer was dried (MgSO) and concentrated in vacuo. The tem, 150 mmx30 mm Phenomonex LUNA C18(2) 10 um 10 column) using an acetonitrile: water gradient 55:45 to 95:5). residue was dissolved in acetonitrile/water (4 ml) and the The appropriate fractions were concentrated in vacuo to give Solution was purified by automated preparative liquid chro the titled compound (24 mg). matography (Gilson system, 150x50 mm, LUNA II C18 10 Experimental MH' 586.0; expected 586.0 1H-NMR um column) using an acetonitrile:Water gradient 55:45 to (CDC13): 1.27-1.30 (9H), 3.21-3.23 (3H), 4.22-4.27 (2H), 15 9:5). The appropriate fractions were concentrated to give the 5.58-5.61 (2H), 7.92-7.95 (2H) titled compound (285 mg). EXAMPLE 53 Experimental MH 561.9; expected 562.0 "H-NMR (DMSO): 3.10-3.14 (3H), 4.46-4.82 (2H), 6.38-6.45 (2H), N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo 7.22-728 (5H), 8.34-8.41 (2H) rothiophenyl)-1H-pyrazol-4-yl)-N-ethylmethane Sulfonamide HC EXAMPLE 55 Cl HN CH 25 3 N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo F Na M FY- s 7s rothiophenyl)-1H-pyrazol-4-yl)-N-(4-fluorobenzyl) S N // no methanesulfonamide F1 N2 O F 30 C Š

To a mixture of Example 38 (200mg 0.42 mmol) and ethyl iodide (67 ul, 0.84 mmol) in acetonitrile (12 ml) was added potassium carbonate (116 mg, 0.84 mmol). The reaction mix 35 ture was then stirred at room temperature for 66 h. The reac F C tion mixture was partitioned between hydrochloric acid (1M) FY. -F NH2 and ethyl acetate and the two layers were separated. The F1 N O organic layer was washed with water, dried (MgSO4) and F N N N^ concentrated in vacuo. The residue was dissolved in acetoni 40 N o a N trile/water (9:1, 6 ml) and the solution was purified by auto C O CH mated preparative liquid chromatography (Gilson system, 150 mmx30 mm Phenomonex LUNA II 10 um C18 column) \ using an acetonitrile:water gradient 60:40 to 95:5). The N appropriate fractions were concentrated in vacuo to give the 45 titled compound (147 mg). Experimental MH 499.9; expected 500.0 'H-NMR (DMSO): 1.03-1.08 (3H), 2.99-3.02 (3H), 3.46-3.54 (2H), To a mixture of Example 38 (200 mg, 0.42 mmol), potas 6.41-6.45 (2H), 8.41-8.44 (2H) sium carbonate (116 mg. 0.84 mmol) and potassium iodide 50 (140 mg. 0.84 mmol) in acetonitrile (12 ml) was added 4-fluo EXAMPLE 54 robenzyl bromide (105ul, 0.84 mmol). The reaction mixture N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo was then stirred at room temperature for 16 h. The reaction rothiophenyl)-1H-pyrazol-4-yl)-N-benzylmethane mixture was partitioned between hydrochloric acid (2M) and Sulfonamide 55 dichloromethane and the two layers were separated. The organic layer was dried (MgSO4) and concentrated in vacuo. F C NH The residue was dissolved in acetonitrile/water (3 ml) and the FY. 1F 2 Solution was purified by automated preparative liquid chro F1I 60 matography (Gilson system, 150x50 mm, LUNA II C18 10 F N N-N-CHS um column) using an acetonitrile:Water gradient 55:45 to N o 2N. C O O 95:5. The appropriate fractions were concentrated to give the titled compound (269 mg). \ 65 Experimental MH 580.0; expected 580.0 'H-NMR (DMSO): 3.10-3.14 (3H), 4.43-4.81 (2H), 6.38-6.45 (2H), 7.08-7.14 (2H), 7.24-7.29 (2H), 8.36-8.41 (2H) US 7,687,533 B2 65 66 EXAMPLE 56 mmol). The reaction mixture was then stirred under nitrogen, at room temperature, overnight. The reaction mixture was N-5-amino-3-cyano-1-2,6-dichloro-4-(trifluorom quenched by addition of methanol and the mixture was con ethyl)phenyl)-1H-pyrazol-4-yl)-1-(methylsulfonyl) centrated in vacuo. The residue was partitioned between ethanesulfonamide dichloromethane and water and the organic phase was sepa CH3 rated, dried and concentrated in vacuo. The residue was dis s/ solved in acetonitrile/water (1.5 ml) and the solution was nNo purified by automated preparative liquid chromatography HC (Gilson system, 150x30 mm, LUNA II C1810 um column) 29 10 using an acetonitrile:water gradient 45:55 to 98:2. The V appropriate fractions were concentrated to give the titled No? N compound (3 mg). Experimental MH 515.9; expected 516.0 'H-NMR 15 (DMSO): 3.50-3.54 (6H), 6.70-6.74 (2H), 7.87-7.91 (1H), 8.08-8.12 (1H), 8.39-8.41 (1H) C Alternative Synthesis To a solution of Preparation 28 (680 mg, 1.89 mmol) in dichloromethane (20 ml) was added triethylamine (1.52 ml, 7.56 mmol), followed by methanesulphonyl chloride (870 F mg, 7.56 mmol). The reaction mixture was then stirred over night at room temperature. The reaction mixture was washed 25 with hydrochloric acid (1N, 50 ml) and the organic phase was To a solution of Example 9 (90 mg, 0.18 mmol) in acetone separated, dried (MgSO4) and concentrated in vacuo. The (3 ml) was added methyl iodide (11 ul, 0.18 mmol) and residue was dissolved in acetonitrile/water (2 ml) and the potassium carbonate (20 mg). The reaction mixture was then Solution was purified by automated preparative liquid chro stirred at room temperature overnight. The reaction mixture matography (Gilson system, 150 mmx30 mm LUNA II C18 was concentrated in vacuo and the residue was partitioned 30 10 um column) using an acetonitrile:water gradient 50:50 to between ethyl acetate (3 ml) and water (3 ml). The organic 95:5. The appropriate fractions were combined and concen phase was then separated, dried and concentrated in vacuo. trated to give the titled compound (37 mg). The crude product was dissolved in a mixture of acetonitrile (0.5 ml) and dimethyl sulphoxide (0.3 ml) and purified by Experimental MH 514.1; expected 514.0 'H-NMR automated preparative liquid chromatography (Gilson sys 35 (DMSO): 3.50-3.54 (6H), 6.70-6.74 (2H), 7.87-7.91 (1H), tem, 150mmx30mm Phenomonex LUNAIIC1810 column) 8.08-8.12 (1H), 8.39-8.41 (1H) using an acetonitrile:water gradient 10:90 to 98:2. The appropriate fractions were concentrated in vacuo to give the titled compound (21 mg). EXAMPLE 58 H-NMR (DMSO): 1.55-1.60 (3H), 3.21-3.22 (3H), 5.20 40 5-amino-1-2,6-dichloro-4-pentafluorothiophenyl-4- 5.26 (1H), 6.38-6.49 (2H), 8.22-8.24 (2H) (1,1-dioxido-1,2-thiazinan-2-yl)-1H-pyrazole-3-car EXAMPLE 57 bonitrile N-5-amino-1-(2-chloro-4-pentafluorothio-phenyl 3-cyano-1H-pyrazol-4-yl)-N-(methylsulfonyl)meth 45 anesulfonamide

50

C 55 C

F F 1. 60 F

F To a solution of Preparation 43 (350 mg, 0.89 mmol) in pyridine (5 ml) was added 4-chlorobutane-1-sulfonyl chlo To a solution of Example 26 (50 mg, 0.09 mmol) in tet 65 rahydrofuran (10 ml), under nitrogen, was added ethylmag ride (WO 2004.050619A1,254 mg, 1.33 mmol). The reaction nesium bromide (3M in tetrahydrofuran, 0.09 ml, 0.27 mixture was then stirred at room temperature for 18 h. The US 7,687,533 B2 67 68 reaction mixture was partitioned between dichloromethane EXAMPLE 60 (20 ml) and water (20 ml) and the organic phase was sepa rated, dried and concentrated in vacuo. To the residue was N-3-cyano-1-2,6-dichloro-4-pentafluorothiophe added N,N-dimethylformamide (5 ml) and potassium car nyl)-4-(methylsulfonyl)(2.2.2-trifluoroethyl)amino bonate (123 mg, 0.89 mmol). The mixture was then heated at 1H-pyrazol-5-yl)-2-methoxyacetamide 850 for 60h. The reaction mixture was concentrated in vacuo and the residue was partitioned between dichloromethane (25 ml) and water (25 ml). The organic phase was separated, dried and concentrated in vacuo. The residue was dissolved in 10 acetonitrile/water (9:1, 2 ml) and the solution was purified by automated preparative liquid chromatography (Gilson sys tem, 150x30 mm, LUNA II C18 10 um column) using an acetonitrile: water gradient 50:50 to 9:5). The appropriate fractions were concentrated to give the titled compound (28 15 mg). Experimental MH 511.9; expected 512.0 'H-NMR (CDC13): 1.98-2.02 (2H), 2.30-2.36 (2H), 3.26-3.30 (2H), 3.73-3.77 (2H), 4.13-4.22 (2H), 7.87-7.90 (2H)

EXAMPLE 59 N-5-(benzylamino)-3-cyano-1-2,6-dichloro-4-pen tafluorothiophenyl)-1H-pyrazol-4-yl)-N-(methylsul 25 fonyl)methanesulfonamide To a solution of Example 32 (200 mg. 0.36 mmol) in acetonitrile (5 ml), at 0°C., was added methoxyacetyl chlo ride (587 mg, 5.4 mmol) and pyridine (142 mg, 1.80 mmol). The reaction mixture was then heated at reflux for 36 h. The 30 reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine, dried (MgSO) and concentrated in vacuo. The residue was dissolved in acetoni trile (3 ml) and the solution was purified by automated pre 35 parative liquid chromatography (Gilson system, 150x30mm, LUNA II C18 10 um column) using an acetonitrile:water CH gradient 60:40 to 98:2. The appropriate fractions were con F C centrated to give the titled compound (164 mg). F-A-1 to--o CH Experimental MH 625.9; expected 626.0 'H-NMR F l N-N/ 3 40 (CDC13): 3.12-3.15 (3H), 3.41-3.44 (3H), 3.82-3.86 (2H), V AñoS 420-4.30 (2H), 7.83-7.86 (2H), 8.74-8.79 (1H) NF O C EXAMPLE 61 ethyl 4-bis(methylsulfonyl)amino-3-cyano-1-2,6- \ 45 dichloro-4-pentafluorothiophenyl)-1H-pyrazol-5- ylimidoformate To a solution of Preparation 44(120 mg, 0.18 mmol) in ethanol (5 ml), at 0°C., was added sodium borohydride (14 mg, 0.36 mmol). The reaction mixture was then allowed to 50 warm to room temperature over 2 h. To the reaction mixture was added hydrochloric acid (2N, 5 ml), followed by water (10 ml) and ethyl acetate (15 ml). The two layers were sepa rated and the aqueous layer was extracted with ethyl acetate (3x15 ml). The combined organic phases were then washed 55 with brine, dried (MgSO) and concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulphoxide (8:2, 2 ml) and the solution was purified by automated pre parative liquid chromatography (Gilson system, 150x30mm, 60 LUNA II C18 10 um column) using an acetonitrile: water gradient 60:40 to 98:2. The appropriate fractions were con centrated to give the titled compound (45 mg). Experimental MH 639.9; expected 640.0 'H-NMR 65 (DMSO): 3.36-3.38 (6H), 4.41-444 (2H), 7.13-7.29 (6H), 8.35-8.36 (2H) US 7,687,533 B2 69 70 To a solution of Example 26 (200 mg, 0.36 mmol) in EXAMPLE 63 triethyl orthoformate (8 ml) was added hydrochloric acid (concentrated, 2 ml). The reaction mixture was then heated at N-3-cyano-1-2,6-dichloro-4-pentafluorothiophe 60° C. for 2 h. The reaction mixture was concentrated in nyl)-4-(methylsulfonyl)(2.2.2-trifluoroethyl)amino vacuo and the residue was washed with toluene. The residue 1H-pyrazol-5-yl)acetamide was dissolved in acetonitrile (2 ml) and the solution was purified by automated preparative liquid chromatography (Gilson system, 150x30 mm, LUNA II C1810 um column) using an acetonitrile:water gradient 55:45 to 95:5). The 10 appropriate fractions were concentrated to give the titled compound (104 mg). Experimental MH 605.9; expected 606.0 'H-NMR (CDC13): 119-124 (3H), 3.41-3.45 (6H), 4.09-4.16 (2H), 7.84-7.87 (2H), 8.23-8.25 (1H) 15 C EXAMPLE 62 N-3-cyano-5-(cyclopropylmethyl)amino]-1-2,6- dichloro-4-pentafluorothiophenyl)-1H-pyrazol-4- p1NFFS-F yl)methanesulfonamide F

25 To a solution of Example 32 (50 mg 0.09 mmol) and 4-dimethylaminopyridine (122 mg, 1.0 mmol) in dichlo romethane (0.5 ml) was added acetic anhydride (0.11 ml, 1.2 mmol) and N,N-dimethylformamide (1 drop). The reaction 30 mixture was then stirred at room temperature for 4 h. The \ CH reaction mixture was partitioned between hydrochloric acid N NN / 3 (1M) and dichloromethane and the organic phase was sepa S rated, washed with water, dried (MgSO) and concentrated in vacuo. The residue was dissolved in acetonitrile (1.5 ml) and purified by automated preparative liquid chromatography 35 (Gilson system, 150 mmx30 mm Phenomonex LUNA C18 C (2) 10um column) using an acetonitrile:Watergradient 55:45 to 95:5). The appropriate fractions were concentrated in vacuo to give the titled compound (34 mg). Experimental MH 596.0; expected 596.0 'H-NMR 40 n F (DMSO): 1.94-198 (3H), 3.16-3.21 (3H), 4.44-4.56 (2H), 1 S NF 8.49-8.53 (2H), 10.38-10.42 (1H) F EXAMPLE 64 N-3-cyano-1-2,6-dichloro-4-pentafluorothiophe To a suspension of Example 26 (100 mg, 0.18 mmol) in 45 nyl-5-methoxy-1H-pyrazol-4- toluene (4 ml) was added molecular sieves (400 mg), cyclo yl)methanesulfonamide propanecarboxaldehyde (40 ul, 0.54 mmol) and p toluenesul phonic (catalytic amount). The reaction mixture was heated at 90°C. for 6h, cooled and concentrated in vacuo. To a solution 50 of the residue in ethanol (4 ml), at 0°C., was added sodium borohydride (16 mg, 0.36 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The residue was dissolved in acetonitrile/water (9:1, 1.5 ml) 55 and purified by automated preparative liquid chromatography (Gilson system, 150 mmx30 mm Phenomonex LUNA C18 (2) 10um column) using an acetonitrile: water gradient 50:50 C to 95:5). The appropriate fractions were concentrated in 60 vacuo to give a mixture of the titled compound (27 mg) and the bis-Sulphonated compound. Experimental MH 526.0; expected 526.0 'H-NMR (CDC13): 0.09-0.13 (2H), 0.44-0.50 (2H), 0.85–0.93 (1H), 65 2.78-2.82 (2H), 3.12-3.16 (3H), 5.95-5.99 (1H), 7.87-7.90 (2H) US 7,687,533 B2 71 72 A mixture of Example 66 (140 mg 0.25 mmol) and sodium Similarly prepared were: hydroxide (1M, 0.5 ml, 0.5 mmol) in tetrahydrofuran (5 ml) was stirred at room temperature for 60 h. To the reaction mixture was added hydrochloric acid (2N, 10 ml) and the O mixture was extracted with ethyl acetate (2x10 ml). The Os, Me combined extracts were dried (MgSO) and concentrated in R2 N vacuo. The residue was dissolved in acetonitrile (1.5 ml) and YSO.Me purified by automated preparative liquid chromatography 10 ( \ (Gilson system, 150 mmx30 mm Phenomonex LUNA C18 YN R5

(2) 10um column) using an acetonitrile: water gradient 50:50 Cla Cl to 95:5). The appropriate fractions were concentrated in vacuo to give the titled compound (67 mg). 15 Experimental MH" 486.8; expected 487.0 'H-NMR (CDC13): 3.19-3.22 (3H), 4.22-4.25 (3H), 5.90-5.94 (1H), SFs 7.84-7.88 (2H) Ex R2 RS From prep 66 CN OMe 29 67 CN nan -CH3 33 EXAMPLE 65 N N-3-cyano-1-2,6-dichloro-4-(trifluoromethyl)phe 25 CH nyl-5-(methylamino)-1H-pyrazol-4-yl)-N-(methyl 68 2-(dimethylamino)ethylamino 32 69 (2-pyrrollidin-1-ylethyl)amino 34 Sulfonyl)methanesulfonamide 70 (2-morpholin-4-ylethyl)amino 31 71 (2-piperidin-1-ylethyl)amino 36 30 72 cyclopropyl NH, 26

EXAMPLE 66

35 N C Šs N H-NMR (CDC13): 3.48-3.52 (6H), 4.07-4.10 (3H), 7.87 O 2- \ 7.90 (2H) On 4 N F Sn S. EXAMPLE 67 / NN F 40 H3C NC Experimental MH 605.0; expected 605.0 'H-NMR o? CH (CDC13): 2.77-2.84 (3H), 2.99-3.05 (3H), 3.34-3.43 (6H), CH3 7.78-7.84 (2H), 8.02-8.07 (1H)

45 EXAMPLE 68 To a mixture of Preparation 30 (35 mg, 0.10 mmol) and triethylamine (28 ul, 0.20 mmol) in dichloromethane (1 ml), Experimental MH 621.0; expected 621.0 'H-NMR at 0°C., was added dropwise methanesulphonyl chloride (16 (CDC13): 2.74-2.79 (6H), 3.20-3.24 (2H), 3.47-3.51 (6H), ul, 0.20 mmol). The reaction mixture was allowed to warm to 50 3.75-3.81 (2H), 7.11-7.17 (1H), 7.85-7.87 (2H) room temperature and stirred for 2 h. To the reaction mixture EXAMPLE 69 was added dichloromethane (5 ml) and the solution was washed with hydrochloric acid (2N, 5 ml) and brine (5 ml), MS (ES): M/Z MH+ 647.0; expected mass for dried (MgSO) and concentrated in vacuo. The residue was 55 C18H21C12F5N6O4S3+H is 647.0 'H-NMR (DMSO): 1.72 1.84 (2H), 1.86-197 (2H), 2.85-2.95 (2H), 3.15-3.22 (2H), dissolved in acetonitrile/dimethylsulphoxide (1:1, 1 ml) and 3.36-3.45 (2H), 3.56-3.64 (8H), 6.88-6.93 (1H), 8.43-8.46 the Solution was purified by automated preparative liquid (2H) chromatography (Gilson system, 250x21.2 mm, LUNA II 60 C185um column) using an acetonitrile:water gradient 45:55 EXAMPLE 70 to 98:2). The appropriate fractions were concentrated to give MS (ES): M/Z MH+ 663.1; expected mass for the titled compound (7 mg). C18H21C12F5N6O5S3+H is 663.0 'H-NMR (CDC13): Experimental MH 505.9; expected 506.0 'H-NMR 65 2.84-2.95 (2H), 3.22-3.28 (2H), 3.37-3.44 (2H), 3.47-3.51 (CDC13): 2.82-2.86 (3H), 3.46-3.49 (6H), 3.78-3.86 (1H), (6H), 3.80-3.89 (4H), 3.91-4.00 (2H), 6.56-6.68 (1H), 7.85 7.75-7.77 (2H) 7.88 (2H) US 7,687,533 B2 73 74 EXAMPLE 71 Similarly prepared was: EXAMPLE 74 MS (ES): M/Z MH+ 661.0; expected mass for C19H23C12F5N6O4S3+H is 661.0 H-NMR (DMSO): N-3-cyano-1-2,6-dichloro-4-pentafluorothiophe nyl-5-(pyridin-4-ylmethyl)amino-1H-pyrazol-4- 1.31-140 (1H), 1.65-1.71 (1H), 1.72-1.79 (4H), 2.80-2.90 yl)methanesulfonamide (2H), 3.11-3.17 (2H), 3.27-3.31 (2H), 3.64-3.67 (6H), 3.67 3.73 (2H), 7.03-7.07 (1H), 8.46-8.48 (2H) 10

EXAMPLE 72

15 Experimental MH" 565.0; expected 565.0 'H-NMR (CDC13): 0.90-0.98 (4H), 1.83-191 (1H), 3.41-3.45 (6H), 3.75-3.89 (2H), 7.82-7.85 (2H) C

EXAMPLE 73 N-5-amino-1-(2,6-dichloro-4-pentafluorothiophe nyl)-1H-pyrazol-4-yl)methanesulfonamide 25

from the compound of Preparation 35 (257 mg, 0.53 mmol) and methanesulphonyl chloride (0.12 ml, 1.59 mmol) to give 30 the title compound (13 mg). Experimental MH 562.9; expected 563.0 'H-NMR (DMSO): 3.03-3.06 (3H), 4.63-4.67 (2H), 7.06-7.11 (1H), 7.40-7.44 (2H), 8.47-8.49 (2H), 8.59-8.63 (2H), 9.10-9.13 (1H) 35 EXAMPLE 75 tert-butyl({5-amino-3-cyano-1-(2,6-dichloro-4-pen C tafluorothiophenyl)-1H-pyrazol-4-yl)amino)sulfo 40 nylcarbamate

45

To a mixture of Preparation 27 (177 mg, 0.33 mmol) and 50 triethylamine (115ul, 0.83 mmol) in dichloromethane (3 ml) and tetrahydrofuran (1 ml) was added methanesulphonyl C chloride (53 ul. 0.83 mmol). The reaction mixture was then stirred at room temperature for 16h. The reaction mixture was 55 washed with hydrochloric acid (1M) and water, dried (MgSO) and concentrated in vacuo to give the crude product. The residue was dissolved in acetonitrile/water (1.2 ml) and the Solution was purified by automated preparative liquid 60 chromatography (Gilson system, 150x50mm, LUNA II C18 A mixture of tert-butanol (0.27 ml, 2.87 mmol) and chlo 10 um column) using an acetonitrile:Water gradient 35:65 to rosulphonyl isocyanate (0.25 ml, 2.87 mmol) in dichlo 95:5). The appropriate fractions were concentrated to give the romethane (12 ml) was stirred at room temperature for 1 h, titled compound (74 mg). before the dropwise addition of Preparation 43 (1.13 g, 2.87 65 mmol) and triethylamine (0.6 ml. 4.31 mmol) in dichlo 'H-NMR (CDC13): 299-3.03 (3H), 3.44-3.47 (2H), 5.74 romethane (12 ml). The reaction mixture was then stirred at 5.83 (1H), 7.53-7.56 (1H), 7.86-7.89 (2H) room temperature for 2 h. The reaction mixture was parti US 7,687,533 B2 75 76 tioned between hydrochloric acid (0.5M) and dichlo Similarly prepared were: romethane and the organic phase was separated, washed with water, dried (MgSO) and concentrated in vacuo. The residue EXAMPLE 77 was purified by column chromatography, eluting with ethyl 5 N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo acetate/cyclohexane 1:9. The appropriate fractions were rothiophenyl)-1H-pyrazol-4-yl)-N-(pyrazin-2-ylm combined and concentrated to give the titled compound (0.62 ethyl)methanesulfonamide g). Experimental MH 573.0; expected 573.0 'H-NMR (DMSO): 1.36-141 (9H), 5.83-5.94 (2H), 8.39-8.42 (2H), 10 9.57-9.60 (1H), 11.07-11.11 (1H) S.

EXAMPLE 76 \N O N-1S-CH N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo 15 rothiophenyl)-1H-pyrazol-4-yl)-N-(2-pyridin-4-yl N K S. ethyl)methanesulfonamide N1 YNH, C C

p1NFne 25 F

from the compound of Example 38 (200 mg, 0.42 mmol) and pyrazin-2-ylmethanol (47 mg, 0.42 mmol) to give the title 30 compound (100 mg). Experimental MH 564.0; expected 564.0 'H-NMR (CDC13): 3.19-3.23 (3H), 4.98-5.06 (2H), 7.87-7.91 (2H), 8.52-8.57 (2H), 8.61-8.66 (1H) 35 EXAMPLE 78 C N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo rothiophenyl)-1H-pyrazol-4-yl)-N-(6-aminopyridin 3-yl)methylmethanesulfonamide 40 NH2 n F 1 S NF F / N S 45 N A mixture of Example 38 (200 mg, 0.42 mmol), 4-(2- \ O hydroxyethyl)pyridine (52 mg, 0.42 mmol) and triph enylphosphine (167 mg, 0.64 mmol) in anhydrous tetrahy NN €h, drofuran (5 ml) was cooled to 0° C. and diethyl ( \ aZodicarboxylate (0.1 ml, 0.64 mmol) was added. The reac 50 N1 YNH, tion mixture was warmed to room temperature and stirred under nitrogen overnight. The reaction mixture was concen C C trated in vacuo and the residue was partitioned between dichloromethane and water. The organic phase was then sepa 55 rated, dried and concentrated in vacuo. The residue was dis solved in acetonitrile/water (4 ml) and the solution was puri fied by automated preparative liquid chromatography (Gilson system, 150x30 mm, LUNA II C1810 um column) using an acetonitrile: 0.1% trifluoroacetic acid gradient 35:65 to 60 95:5). The appropriate fractions were concentrated to give the from the compound of Example 38 (200 mg, 0.42 mmol) and titled compound (55 mg). (6-aminopyridin-3-yl)methanol (WO 2003000682 A1, 53 mg, 0.43 mmol) to give the title compound (82 mg). Experimental MH 577.0; expected 577.0 'H-NMR Experimental MH 578.0; expected 578.0 'H-NMR (CDC13): 299-3.04 (3H), 3.11-3.18 (2H), 4.12-4.17 (2H), 65 (DMSO): 3.15-3.21 (3H), 4.34-4.47 (1H), 4.61-4.75 (1H), 4.19-4.41 (2H), 7.62-7.69 (2H), 7.86-7.89 (2H), 8.59-8.67 6.48-6.57 (2H), 6.91-6.95 (1H), 7.69-7.73 (1H), 7.78-7.83 (2H) (1H), 7.91-8.10 (2H), 8.41-8.47 (2H) US 7,687,533 B2 77 78 EXAMPLE 79 To a mixture of Preparation 40 (505 mg, 0.91 mmol) and N-3-cyano-1-2,6-dichloro-4-pentafluorothiophe potassium carbonate (800 mg, 5.80 mmol) in acetonitrile (10 nyl)-1H-pyrazol-4-yl)-2-oxo-N-(2.2.2-trifluoroethyl) ml) was added dropwise 2.2.2-trifluoroethyl trichlo propane-1-sulfonamide romethane sulphonate (0.30 ml, 1.83 mmol). The reaction F mixture was then heated at 40° C. for 19 h. The reaction F H3C O F mixture was partitioned between ethyl acetate and water and the two layers were separated. The aqueous layer was \\ N-S r 10 extracted with ethyl acetate and the combined organic phases so were washed with Saturated Sodium hydrogencarbonate solu tion and brine, dried (MgSO) and concentrated in vacuo. The NN| \ 0 N residue was dissolved in acetonitrile (2 ml) and the solution 15 was purified by automated preparative liquid chromatogra C C phy (Gilson system, 150x30 mm, LUNA II C1810 um col umn) using an acetonitrile: 0.1% trifluoroacetic acid gradient 40:60 to 95:5). The appropriate fractions were concentrated FN-F to give the trifluoroacetate salt of the desired compound. A p1NF solution of the trifluoroacetate salt in dichloromethane (10 F ml) was washed with Saturated aqueous sodium hydrogencar To a solution of Preparation 47 (192 mg 0.29 mmol) in bonate solution (10 ml) and brine, dried (MgSO) and con tetrahydrofuran (2 ml), at -30°C., was added dropwise iso 25 centrated in vacuo. To a solution of the residue in diethyl ether propylmagnesium chloride (2M in tetrahydrofuran, 0.16 ml, (5 ml) and methanol (1 drop) was added hydrogen chloride in 0.32 mmol). After 30 min, acetylchloride (41 ul, 0.58 mmol) was added via Syringe and the reaction mixture was allowed diethyl ether (2 ml). The reaction mixture was then stirred for to warm to room temperature and stirred for 2 h. To the 5 min and concentrated in vacuo. To the residue was added reaction mixture was added hydrochloric acid (2N, 10 ml) 30 acetonitrile (3 ml) and water (0.5 ml) and the solution was and the mixture was extracted with ethyl acetate (2x10 ml). The combined extracts were dried (MgSO) and concentrated freeze-dried to give the titled compound (35 mg). in vacuo to give a mixture of products. The residue was Experimental MH 639.1; expected 639.0 'H-NMR dissolved in acetonitrile (1 ml) and purified by automated (DMSO): 2.62-2.65 (6H), 2.95-3.11 (2H), 3.29-3.30 (4H), preparative liquid chromatography (Gilson system, 250 35 mmx30 mm Phenomonex LUNA C18(2) 10 um column) 3.35-3.37 (3H), 4.55-4.63 (2H), 8.52-8.54 (2H) using an acetonitrile: 0.1% trifluoroacetic acid gradient 60: 40 to 98:2. The appropriate fractions were concentrated in EXAMPLE 81 vacuo to give a mixture of the titled compound (15 mg) and other products. 40 hydrochloride salt of N-3-cyano-1-(2,6-dichloro-4- Experimental MH 580.9; expected 581.0 'H-NMR pentafluorothiophenyl-5-(2-piperidin-1-ylethyl) (CDC13): 2.36-2.39 (3H), 4.17-4.20 (2H), 4.30-4.38 (2H), 7.88-7.92 (3H) amino)-1H-pyrazol-4-yl)-N-(2.2.2-trifluoroethyl) EXAMPLE 8O methanesulfonamide

hydrochloride salt of N-(3-cyano-1-2,6-dichloro-4- 45 pentafluorothiophenyl-5-3-(dimethylamino)ethyl amino)-1H-pyrazol-4-yl)-N-(2,2,2-trifluoroethyl) methanesulfonamide F F F F 50 F F

O \ O \N N4 N N4 55 so ? \ CH3so \CH3 ? \ CH3 YN 1N1 YCH, N NH V C cCH3 C C 60

'n' p1NFne F1 NF 65 F US 7,687,533 B2 79 80 from the compound of Preparation 41 (420 mg. 0.72 mmol) To a mixture of Example 15 (200 mg, 0.48 mmol), 4-dim and 2.2.2-trifluoroethyl trichloromethane sulphonate (0.30 ethylaminopyridine (20 mg) and pyridine (0.2 ml) in dichlo ml, 1.83 mmol) to give the title compound (175 mg). MS (ES): M/Z MH+ 665.1; expected mass for romethane (4 ml) was added 4-fluorobenzenesulphonyl chlo C20H22C12F8N6O2S2+H is 665.1 H-NMR (DMSO): 5 ride (93 mg 0.48 mmol). The reaction mixture was then 1.63-1.74 (4H), 2.72-2.85 (2H), 3.01-3.08 (2H), 3.21-3.28 stirred overnight at room temperature. The reaction mixture (4H), 3.30-3.33 (3H), 3.47-3.77 (2H), 4.43-4.52 (2H), 6.74 6.79 (1H), 8.41-8.45 (2H) was partitioned between ethyl acetate (25 ml) and water (25 EXAMPLE 82 ml) and the two layers were separated. The organic layer was 10 then dried (NaSO) and concentrated in vacuo. The residue N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo rothiophenyl)-1H-pyrazol-4-yl)sulfamide was purified using an IsoluteTM cartridge (silica, 25 g) with gradient elution, ethyl acetate:cyclohexane 15:85 to 1:1. N NH2 The appropriate fractions were combined and concentrated to 15 give the titled compound (55 mg). Experimental MH 571.9; expected 572.0 "H-NMR (DMSO): 3.69-3.75 (3H), 6.63-6.70 (2H), 7.51-7.57 (2H), 7.89-7.95 (2H), 8.19-8.29 (2H) Similarly prepared was:

F F EXAMPLE 84 1. 25 F N-5-amino-3-cyano-1-(2,6-dichloro-4-(trifluorom ethyl)phenyl)-1H-pyrazol-4-yl)-2,4-difluoro-N-(me To a solution of Example 75 (150 mg, 0.26 mmol) in thylsulfonyl)benzenesulfonamide dichloromethane (2.4 ml), at 0°C., was added trifluoroacetic acid (0.6 ml, 7.79 mmol). The reaction mixture was then 30 stirred at room temperature for 2.5 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in acetonitrile/water (2 ml). The solution was purified by auto mated preparative liquid chromatography (Gilson system, 150x30 mm, LUNA II C1810 um column) using an acetoni 35 trile:water gradient 40:60 to 95:5). The appropriate fractions were concentrated to give the titled compound (77 mg). Experimental MH 472.8; expected 473.0 H-NMR (DMSO): 6.02-6.07 (2H), 6.81-6.85 (2H), 8.41-8.44 (2H), 8.51-8.57 (1H) 40 EXAMPLE 83 N-5-amino-3-cyano-1-2,6-dichloro-4-(trifluorom ethyl)phenyl)-1H-pyrazol-4-yl)-4-fluoro-N-(methyl sulfonyl)benzenesulfonamide 45

C 50

55

C 60 from the compound of Example 15 (200 mg, 0.48 mmol) and 2,4-difluorobenzenesulphonyl chloride (102 mg, 0.48 mmol) to give the title compound (50 mg).

65 Experimental MH 589.9; expected 590.0 'H-NMR (CDC13): 3.58-3.60 (3H), 4.26-4.34 (2H), 7.00-7.10 (2H), 7.75-7.82 (2H), 7.92-8.01 (1H) US 7,687,533 B2 81 82 EXAMPLE 85 from N-5-amino-3-cyano-1-2,6-dichloro-4-pentafluo rothiophenyl)-1H-pyrazol-4-yl)-N-(2,2,2-trifluoroethyl) methyl 3-cyano-1-2,6-dichloro-4-pentafluo rothiophenyl)-4-(methylsulfonyl)(2.2.2-trifluoroet methanesulfonamide (100 mg 0.18 mmol) and ethylene hyl)amino)-1H-pyrazol-5-ylcarbamate diamine (1 ml) to give the title compound (12 mg). CH. F. F Experimental MH 640.0; expected 640.0 'H-NMR (CD3OD): 3.23-3.26 (3H), 3.75-3.81 (2H), 3.94-3.99 (2H), 4.11-4.14 (2H), 8.20-8.23 (2H) 10

EXAMPLE 87

C trifluoroacetate salt of N-5-[(2-azetidin-1-ylethyl) 15 amino-3-cyano-1-2,6-dichloro-4-pentafluo rothiophenyl)-1H-pyrazol-4-yl)-N-(2.2.2-trifluoroet hyl)methanesulfonamide

To a solution of N-(5-amino-3-cyano-1-2,6-dichloro-4- pentafluorothiophenyl)-1H-pyrazol-4-yl)-N-(2.2.2-trifluo roethyl)methanesulfonamide (200 mg 0.6 mmol), pyridine 25 O CH. F. F (73 ul. 0.90 mmol) and 3 A molecular sieves (0.2 g) in tolu S. enefdichloromethane (2:3, 3.6 ml), at 0°C., was added phos N S gene (20% in toluene, 1.7M, 2 ml). After stirring for 1 h at 0° \ 21\ F C. methanol (2 ml) was added and the reaction mixture was N allowed to warm to room temperature. The reaction mixture 30 was concentrated in vacuo to give the crude product. The crude product was dissolved in acetonitrile/dimethyl sul (YN \ 1N-1 O phoxide (1 ml) and the solution was purified by automated H preparative liquid chromatography (Gilson system, 250x30 C C mm, LUNA II C1810 um column) using an acetonitrile:0.1% 35 trifluoroacetic acid gradient 55:45 to 95:5). The appropriate fractions were concentrated to give the titled compound (12 mg). Experimental MH 612.1; expected 612.0 'H-NMR n:- (DMSO): 3.18-3.22 (3H), 3.54-3.58 (3H), 4.44-4.60 (2H), 40 p1NF 8.51-8.55 (2H), 10.30-10.35 (1H) F Similarly prepared were:

EXAMPLE 86 45 To a mixture of Preparation 48 (120 mg 0.20 mmol), N-5-((2-aminoethyl)aminocarbonyl)amino)-3- sodium triacetoxyborohydride (43 mg, 0.20 mmol) and aze cyano-1-2,6-dichloro-4-pentafluorothiophenyl)-1H pyrazol-4-yl)-N-(2,2,2-trifluoroethyl)methane tidine (14 ul, 0.20 mmol) in dichloromethane (2 ml) was Sulfonamide added acetic acid (11 ul, 0.20 mmol). The reaction mixture 50 was then stirred at room temperature for 72 h. The reaction O F mixture was partitioned between aqueous Sodium hydrogen N he 4” F carbonate solution and ethyl acetate. The organic layer was \ Y F separated, dried (MgSO4) and concentrated in vacuo. The 55 residue was dissolved in acetonitrile/water (1 ml) and the Solution was purified by automated preparative liquid chro matography (Gilson system, 150x30 mm, LUNA II C18 10 um column) using an acetonitrile: 0.2% trifluoroacetic acid 60 gradient 40:60 to 95:5). The appropriate fractions were con centrated to give the titled compound (28 mg). Experimental MH 637.1; expected 637.0 'H-NMR (CDC13): 2.30-2.42 (1H), 2.58-2.71 (1H), 3.18-3.22 (3H), 65 3.35-3.49 (2H), 3.74-3.84 (1H), 3.85-4.00 (2H), 4.09-4.19 (1H), 4.21-4.33 (3H), 4.40-4.54 (1H), 6.54-6.63 (1H), 7.82 7.88 (2H) US 7,687,533 B2 83 84 EXAMPLE 88 roethyl)methanesulfonamide (250 mg, 0.45 mmol) and cop per (II) chloride (303 mg, 2.25 mmol) in acetonitrile (5 ml) N-(3-cyano-1-2,6-dichloro-4-pentafluorothiophe was added tert-butyl nitrite (102 ul, 0.68 mmol) in acetonitrile nyl)-5-[(2,4-dihydroxyphenyl)methylenelamino (1 ml). The reaction mixture was then stirred at room tem 1H-pyrazol-4-yl)-N-(2.2.2-trifluoroethyl)methane 5 perature for 3 h. The reaction mixture was concentrated in Sulfonamide vacuo and the residue was partitioned between ethyl acetate (10 ml) and water (10 ml). The two layers were separated and OH the aqueous layer was extracted with ethyl acetate (10 ml). The combined organic phases were then dried (MgSO) and 10 concentrated in vacuo. The residue was dissolved in acetoni trile (1 ml) and the solution was purified by automated pre parative liquid chromatography (Gilson system, 150x30mm,

LUNA II C18 10 um column) using an acetonitrile:water gradient 60:40 to 95:5). The appropriate fractions were con 15 centrated to give the titled compound (58 mg). 'H-NMR (CDC13): 3.21-3.25 (3H), 4.22-4.30 (2H), 7.90 7.93 (2H) EXAMPLE 90 N-(3-cyano-1-2,6-dichloro-4-pentafluorothiophe nyl-5-3-(dimethylamino)ethylamino)-1H-pyra Zol-4-yl)-N-(methylsulfonyl)methanesulfonamide A mixture of N-(5-amino-3-cyano-1-(2,6-dichloro-4-pen tafluorothiophenyl)-1H-pyrazol-4-yl)-N-(2.2.2-trifluoroet 25 hyl)methanesulfonamide (500 mg, 0.9 mmol), 2,3-dihy droxybenzaldehyde (248 mg, 1.8 mmol), molecular sieves O and p-toluenesulphonic acid (17 mg) in toluene (15 ml) was On 4 heated at reflux overnight. The reaction mixture was concen N cS trated in vacuo and the residue was washed with water, ethyl \HC V O acetate and brine, dried (MgSO4) and concentrated in vacuo. 30 N4 The residue was dissolved in acetonitrile/dimethyl sulphox ) \( CHSo -CH3 ide (1 ml) and the solution was purified by automated pre N N parative liquid chromatography (Gilson system, 150x50mm, N N N V LUNA II C18 10 um column) using an acetonitrile: water V CH gradient 65:35 to 95:5). The appropriate fractions were con 35 C CCH3 centrated to give the titled compound (200 mg). Experimental MH 673.9; expected 674.0 'H-NMR (DMSO): 3.29-3.31 (3H), 4.49-4.57 (2H), 6.13-6.17 (1H), 6.25-6.29 (1H), 7.34-7.39 (1H), 8.52-8.54 (2H), 8.87-8.90 (1H) 40 p1NFn:- EXAMPLE 89 F N-5-chloro-3-cyano-1-2,6-dichloro-4-pentafluo To a mixture of Preparation 33 (550 mg, 1.0 mmol) and rothiophenyl)-1H-pyrazol-4-yl)-N-(2.2.2-trifluoroet 45 triethylamine (0.33 ml, 2.3 mmol) in dichloromethane (15 hyl)methanesulfonamide ml), at 0°C., was added dropwise methanesulphonyl chloride (0.19 ml, 2.3 mmol). The reaction mixture was allowed to F F warm to room temperature and stirred for 16 h. To the reaction mixture was added water (10 ml) and the two layers were separated. The aqueous layer was extracted with dichlo romethane (2x20 ml) and the combined organic phases were N-S-CH washed with brine, dried (MgSO) and concentrated in vacuo to the titled compound (600mg). Experimental MH 635.0; expected 635.0 55 The following Preparations illustrate the synthesis of cer tain intermediates used in the preparation of the preceding C C Examples. Preparation 1 60 N-(3-cyano-1-2,6-dichloro-4-(trifluoromethyl)phe ni nyl-5-(dimethylamino)methylenelamino)-1H p1NF pyrazol-4-yl)-3,4-difluorobenzenesulfonamide F 65 To a solution of Preparation 51 (200 mg, 0.51 mmol) in To a mixture of N-(5-amino-3-cyano-1-2,6-dichloro-4- dichloromethane (4 ml) was added 4-dimethylaminopyridine pentafluorothiophenyl)-1H-pyrazol-4-yl)-N-(2.2.2-trifluo (20 mg), pyridine (0.2 ml) and 3,4-difluorobenzenesulphonyl US 7,687,533 B2 85 chloride (163 mg, 0.77 mmol). The reaction mixture was then Similarly prepared were: stirred at room temperature overnight. The reaction mixture was concentrated under a stream of nitrogen to give the titled compound (200 mg), as a mixture of mono- and bis-Sulpho nated product. O Sa R3 Experimental MH" 567.1; expected 567.0 N st Similarly prepared from Preparation 51 (except for Prepa \ ration 4, which was prepared from Preparation 23) were: YR4 10 NS an -CH3 N N

Cla Cl CH3

15

O Sa R3 N\ stN R1a. NH From MS (ES): M/Z Prep (MH+] NN an -CH3 Prep R1a R4 R3 no. (expected mass) N N 7 CF; cyanomethyl Me 15 508.3; (508.0) 8 pyridin-2- Me " 560.4; (560.1) C C CH3 25 ylmethyl 9 Benzyl Me 559.4; (559.1) 10 2-hydroxyethyl Me 515.0; (513.1) 11 methylthio- Me 531.0; (529.0) methyl 12 cycleobutyl trifluoromethyl 16 577.0; (577.1) R1a. 13 2-N,N- Me 15 540.0; (540.1) 30 dimethyl aminoethyl MS (ES): M/Z 14 SFs Me trifluoromethyl 45 594.9; (595.0) MH+] Prep R1a. R3 (expected mass) 35 Preparation 15 2 CF methylsulfonylmethyl 547.0 (547.0) N-(3-cyano-1-2,6-dichloro-4-(trifluoromethyl)phe 3 SFs Me 527.0 (527.0) nyl-5-(dimethylamino)methylenelamino)-1H 4 CF benzyl 547.1 (545.1) pyrazol-4-yl)methanesulfonamide 5 2-phenylethenyl 555.2 (555.0) 40 To Preparation 19 (3.4 g. 6.21 mmol) in a mixture of tetrahydrofuran (35 ml) and methanol (35 ml) was added potassium carbonate (2.15g, 15.53 mmol). The reaction mix ture was then stirred at room temperature for 2 h. Preparation 6 45 The reaction mixture was concentrated in vacuo and to the residue was added ethyl acetate. The solution was washed with hydrochloric acid (1N) and brine and then concentrated N-(3-cyano-1-2,6-dichloro-4-(trifluoromethyl)phe in vacuo. The residue was purified by column chromatogra nyl-5-(dimethylamino)methylenelamino)-1H 50 phy (silica, 50 g) with gradient elution, dichloromethane: pyrazol-4-yl)-N-(cyclopropylmethyl)methane methanol 100:0 to 95:5). The appropriate fractions were combined and concentrated to give the titled compound (620 Sulfonamide mg). 'H-NMR (DMSO): 2.67-2.70 (3H), 2.90-2.95 (3H), 2.99 55 3.02 (3H), 8.19-8.23 (2H), 8.30-8.33 (1H), 9.43-9.47 (1H) To a solution of Preparation 15 (100 mg 0.21 mmol) in acetone (4 ml) was added potassium carbonate (38 mg, 0.28 Preparation 16 mmol), followed by bromocyclopropane (25 ul, 0.26 mmol). The reaction mixture was then heated at reflux for 2 h. The N-(3-cyano-1-2,6-dichloro-4-(trifluoromethyl)phe reaction mixture was concentrated under nitrogen and the 60 nyl-5-(dimethylamino)methylenelamino)-1H residue partitioned between ethyl acetate and water. The two pyrazol-4-yl)-1,1,1-trifluoromethanesulfonamide layers were separated and the aqueous layer was extracted To a solution of Preparation 46 (650 mg, 0.99 mmol) in with ethyl acetate (x2). The combined organic phases were trifluoroethanol (9 ml) was added aqueous sodium hydroxide dried (MgSO4) and concentrated under nitrogen to give the 65 solution (2.5N, 16 drops). The reaction mixture was then titled compound (100 mg). stirred at room temperature, under nitrogen, for 1 h. To the Experimental MH" 523.4; expected 523.1 reaction mixture was added hydrochloric acid (2M, 2 ml) and US 7,687,533 B2 87 88 the solution was concentrated in vacuo. The residue was washed with water (2x200 ml) and brine (200 ml), dried partitioned between ethyl acetate (20 ml) and water (20 ml) (MgSO) and concentrated in vacuo. The residue was purified and the two phases were separated. The organic phase was by column chromatography (silica, 250 g) with gradient elu washed with water (2x20 ml), dried (NaSO) and concen tion, ethyl acetate:dichloromethane 0:1 to 1:4. The appro trated in vacuo to give the titled compound (505 mg). priate fractions were combined and concentrated to give the Experimental MH" 523.2; expected 523.0 titled compound (2.6 g). Preparation 17 Experimental MH" 449.0; expected 449.0

N-(3-cyano-1-2,6-dichloro-4-(trifluoromethyl)phe 10 Alternative Synthesis nyl-5-(dimethylamino)methylenelamino)-1H A solution of Preparation 55 (10.0g, 21.0 mmol) in metha pyrazol-4-yl)-N-(methylsulfonyl)cyclopropane nol (300 ml) was placed under a hydrogen atmosphere (50 Sulfonamide psi), with platinum (5% on charcoal, 1 g), at room tempera ture for 2 h. The reaction mixture was filtered and concen To a solution of Preparation 15 (150 mg, 0.32) and triethy 15 trated in vacuo and the residue was triturated with diethyl lamine (66 ul, 0.48 mmol) in dichloromethane (3 ml) was ether. The solution was concentrated in vacuo to give the titled added cyclopropanesulphonyl chloride (35 mg 0.48 mmol). compound (8.5 g). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated in vacuo 'H-NMR (CDC13): 2.74-2.78 (3H), 2.96-2.99 (3H), 7.76 and the residue was purified using an IsoluteTM cartridge 7.81 (2H), 8.18-8.21 (1H) (silica, 10 g) with gradient elution, cyclohexane:ethyl acetate 3:1 to 1:1. The appropriate fractions were combined and Preparation 24 concentrated to give the titled compound (150 mg). Experimental MH" 572.9; expected 573.0 N-(3-cyano-1-2,6-dichloro-4-pentafluorothiophe Similarly prepared were: 25 nyl-5-(dimethylamino)methylenelamino)-1H pyrazol-4-yl)-N-(2.2.2-trifluoroethyl)methane Sulfonamide O Os. - Me 30 To a solution of Preparation 3 (239 mg, 0.45 mmol) in 1-methyl-2-pyrrolidinone (4 ml) was added sodium hydride R2 N (60% in oil, 12 mg 0.50 mmol). The mixture was stirred at YR4 room temperature for 5 min and 2.2.2-trifluoroethyltrichlo romethane sulphonate (166 mg, 0.59 mmol) was added. The NN 21N 1. CH 35 N N reaction mixture was then stirred overnight at room tempera ture. To the reaction mixture was added brine (10 ml) and the Cl Cl CH mixture was adjusted to pH4 by addition of hydrochloric acid (2N). The mixture was extracted with ethyl acetate (2x10 ml) 40 and the combined extracts were dried (MgSO) and concen trated in vacuo. The residue was purified by column chroma R1a. tography (silica) eluting with ethyl acetate/hexane 1:3). The appropriate fractions were combined and concentrated to give From MS (ES): M/Z MH+] the titled compound (82 mg). Prep R1a. R2 R4 prep (expected mass) 45 Experimental MH 609.0; expected 609.0 18 CF CN N,N- 15 575.9; (576.0 dimethylamino sulfonyl Preparation 25 19 methylsulfonyl 51 547.4; (547.1) 2O SFs CF 71 647.9; (648.0) 50 N-(3-cyano-1-2,6-dichloro-4-pentafluorothiophe 21 OCF, CN 72 578.9; (579.0) nyl-5-(dimethylamino)methylenelamino)-1H 22 OCHF, 73 544.9; (545.0) pyrazol-4-yl)-N-1-(trifluoromethyl)cyclopropyl methylmethanesulfonamide Preparation 23 55 To a solution of Preparation 3 (147 mg, 0.28 mmol) in N'-(4-amino-3-cyano-1-(2,6-dichloro-4-pentafluo acetonitrile (6 ml) was added Preparation 52 (107 mg, 0.36 rothiophenyl)-1H-pyrazol-5-yl-N,N-dimethylimido mmol) in acetonitrile (2 ml), followed by caesium carbonate formamide (91 mg, 0.59 mmol) and potassium iodide (catalytic amount). 60 The reaction mixture was then heated at reflux for 5 h. The To a solution of Preparation 53 (9.0 g, 15.15 mmol) in reaction mixture was concentrated in vacuo and the residue tetrahydrofuran (120 ml) was added tetrabutylammonium was partitioned between water (10 ml) and ethyl acetate (15 fluoride (60.6 ml, 60.6 mmol) over 5 min. The reaction mix ml). The two layers were separated and the aqueous layer was ture was heated at 50° C. for 1 h and then allowed to cool to adjusted to pH 1 by addition of hydrochloric acid (2N) and room temperature. The reaction mixture was concentrated in 65 re-extracted with ethyl acetate (10 ml). The combined organic vacuo and the residue was partitioned between ethyl acetate phases were dried (MgSO) and concentrated in vacuo. The (200 ml) and water (200 ml). The organic layer was separated, residue was purified by column chromatography (silica) with US 7,687,533 B2 89 90 gradient elution, ethyl acetate:hexane 1:4 to 1:2. The appro calcium chloride (13 mg, 0.11 mmol) and water (0.5 ml). The priate fractions were combined and concentrated to give the reaction mixture was heated at reflux for 6 hand then stirred titled compound (155 mg). at room temperature for 8 h. The reaction mixture was filtered Experimental MH 649.0; expected 649.0 through Celite R, washing through with ethyl acetate, and the filtrate was concentrated in vacuo. To the residue was added Preparation 26 ethyl acetate and the solution was washed with saturated aqueous Sodium hydrogencarbonate solution (10 ml) and 3-cyclopropyl-1-2,6-dichloro-4-pentafluorothiophe brine (10 ml), dried (MgSO) and concentrated in vacuo to nyl)-1H-pyrazole-4,5-diamine give the titled compound (35 mg). 10 Experimental MH 349.9; expected 350.0 To a solution of Preparation 56 (150 mg. 0.30 mmol) in Similarly prepared were: ethanol (5 ml) was added tin(II) chloride (288 mg, 1.52 mmol). The reaction mixture was heated at reflux for 6 h, cooled and hydrochloric acid (6N, 0.5 ml) was added. The reaction mixture was then heated at reflux for a further 16 h. 15 To the reaction mixture was added ethylacetate (25 ml), water \N NH2 and saturated aqueous Sodium hydrogencarbonate solution. The two layers were separated and the organic layer was dried Y \ 2 (MgSO) and concentrated in vacuo to give the titled com NS -R pound as a mixture of products. N N Experimental MH 409.0; expected 409.01 Y: Similarly prepared were: C C

25 R2 NH2 F-1 F F1 NF ( \ F N1 YNH, From MS (ES): M/Z MH+] 30 Prep R3a R4a prep (expected mass) R C 31 H 2-morpholin-4-ylethyl 66 507.0; (507.1) 32 H 2-N,N-dimethylaminoethyl 67 465.1; (465.1) 33 Me 2-N,N-dimethylaminoethyl 70 479.0; (479.1) 34 H 2-pyrrollidin-1-ylethyl 68 491.0; (491.1) 35 35 H Pyridin-4-ylmehtyl 60 485.0; (485) 'n'- F 36 H 2-piperidin-1-ylethyl 69 505.0; (505.1) F1 NF F From prep MS (ES): M/Z MH+] Preparation 37 Prep R1b. R2 lO. (expected mass) 40 4-bis(methylsulfonyl)amino-1-2,6-dichloro-4- 27 C H 57 369.0: (369.0) pentafluorothiophenyl-5-(dimethylamino)methyl 28 H CN 58 360.0; (360.0) enelamino)-1H-pyrazole-3-carboxamide 45 Hydrogen chloride was bubbled through methanol (8 ml) Preparation 29 for 10 min. To the solution was added Example 67 (441 mg, 0.73 mmol) and the flow of hydrogen chloride was main 4-amino-1-2,6-dichloro-4-pentafluorothiophenyl-5- tained for a further 5 min. The reaction mixture was then methoxy-1H-pyrazole-3-carbonitrile sealed and left overnight. The reaction mixture was concen 50 trated in vacuo and to the residue was added methanol (20 ml) To a solution of Preparation 59 (530 mg, 1.21 mmol) in and hydrochloric acid (2N, 10 ml). The mixture was stirred ethanol (10 ml) was added tin(II) chloride (1.14 g. 6.05 for 1 h and water (30 ml) was added. The mixture was mmol), followed by hydrochloric acid (6N, 1 ml). The reac extracted with ethyl acetate (3x20 ml) and the combined tion mixture was then heated at reflux for 2 h. The reaction extracts were dried (MgSO) and concentrated in vacuo to mixture was concentrated in vacuo and to the residue was 55 give the titled compound (450 mg) as a 20:1 mixture of the added ethyl acetate (40 ml). The solution was then washed amide and the methyl ester. with water (30 ml) and brine (30 ml), dried (MgSO) and Experimental MH 623.0; expected 623.0 concentrated in vacuo to give the titled compound (495 mg). Experimental MH" 408.9; expected 409.0 Preparation 38 60 Preparation 30 N-(3-acetyl-1-2,6-dichloro-4-pentafluorothiophe nyl-5-(dimethylamino)methylenelamino)-1H 4-amino-1-2,6-dichloro-4-(trifluoromethyl)phenyl pyrazol-4-yl)-N-(methylsulfonyl)methanesulfona 5-(methylamino)-1H-pyrazole-3-carbonitrile mide 65 To a solution of Preparation 65 (40 mg, 0.11 mmol) in To a solution of Example 67 (500 mg. 0.83 mmol) in ethanol (2.5 ml) was added iron powder (57 mg, 1.0 mmol), tetrahydrofuran (10 ml), at 0°C., was added dropwise meth US 7,687,533 B2 91 92 ylmagnesium bromide (3M in diethyl ether, 0.8 ml, 2.48 The organic phase was separated, dried (MgSO4) and con mmol). The reaction mixture was then stirred at room tem centrated in vacuo to give the titled compound (155 mg). perature for 2 days. The reaction mixture was poured onto ice, Experimental MH 622.0; expected 622.0 water and hydrochloric acid (2N). The mixture was stirred for 30 min and then extracted with ethyl acetate (3x30 ml). The 5 combined extracts were dried (MgSO) and concentrated in Preparation 43 vacuo. The residue was dissolved in acetonitrile (2 ml) and the Solution was purified by automated preparative liquid 4,5-diamino-1-2,6-dichloro-4-pentafluorothiophe chromatography (Gilson system, 150x30mm, LUNA II C18 nyl)-1H-pyrazole-3-carbonitrile 10 um column) using an acetonitrile:water gradient 50:50 to 10 95:5). The appropriate fractions were concentrated to give the To a solution of Preparation 23 (300 mg, 0.67 mmol) in titled compound (97 mg). methanol (8 ml) and dioxane (1 ml) was added hydrochloric Experimental MH" 622.0; expected 622.0 acid (2M, 8 ml). The reaction mixture was then heated at Preparation 39 15 reflux overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate N-5-amino-3-cyano-1-2,6-dichloro-4-(trifluo and water. The organic layer was separated, dried (MgSO4) romethoxy)phenyl)-1H-pyrazol-4- and concentrated in vacuo to give the titled compound (273 yl)methanesulfonamide mg). Experimental MH 394.0; expected 394.0 To a solution of Example 35 (120 mg, 0.24 mmol) in tetrahydrofuran (5 ml) was added aqueous sodium hydroxide Preparation 44 solution (1M, 4.25 ml) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified N-(3-cyano-1-2,6-dichloro-4-pentafluorothiophe by addition of hydrochloric acid (1M) and then extracted with 25 dichloromethane. The combined extracts were dried nyl-5-phenylmethylenelamino)-1H-pyrazol-4-yl)- (NaSO4) and concentrated in vacuo to give the titled com N-(methylsulfonyl)methanesulfonamide pound (100 mg). Experimental MH" 429.9; expected 430.0 To a solution of Example 26 (100 mg, 0.18 mmol) in Similarly prepared were: 30 toluene (5 ml) was added benzaldehyde (0.04 ml, 0.36 mmol), p-toluenesulphonic acid (catalytic amount) and some 4 A molecular sieves. The reaction mixture was heated at 90° C. N for 8 h and then stirred at room temperature for 15 h. The 35 reaction mixture was concentrated in vacuo and the residue \ . n SN was partitioned between ethyl acetate (10 ml) and water (10 f \ WCH, ml). The two layers were separated and the aqueous layer was NN N R5a extracted with ethyl acetate (2x10 ml). The combined organic 40 phases were washed with brine, dried (MgSO) and concen C C trated in vacuo to give the titled compound (120 mg). Experimental MH 637.9; expected 638.0

45 Preparation 45 SFs N-(3-cyano-1-2,6-dichloro-4-pentafluorothiophe From MS (ES): M/Z MH+] Prep R5a prep (expected mass) nyl-5-(dimethylamino)methylenelamino)-1H pyrazol-4-yl)-1,1,1-trifluoromethanesulfonamide 40 (2-(dimethylamino)ethyl) 111 557.0; (557.0) 50 (methyl)amino 41 (2-piperidin-1-ylethyl)amino Ex 71583.0; 583.1 To a solution of Preparation 23 (200 mg, 0.45 mmol) in anhydrous dichloromethane (5 ml), at 0°C., was added tri ethylamine (124 ul, 0.89 mmol) and trifluoromethanesul Preparation 42 55 phonic anhydride (150 ul, 0.89 mol). The reaction mixture N-(3-cyano-1-2,6-dichloro-4-pentafluorothiophe was then stirred under nitrogen for 30 min. To the reaction nyl-5-(dimethylamino)methylenelamino)-1H mixture was added dichloromethane and hydrochloric acid pyrazol-4-yl)-N-2-(1H-1,2,4-triazol-1-yl)ethyl (4M, 3 ml). The organic phase was separated, washed with methanesulfonamide 60 hydrochloric acid (4M) and brine, dried (Na2SO) and con centrated in vacuo. The residue was purified by column chro To a mixture of Preparation 74 (154 mg., 0.24 mmol) and matography (silica, 25 g) with gradient elution, ethyl acetate: 1,2,4-triazole (42 mg, 0.61 mmol) in acetonitrile (10 ml) was cyclohexane 2:1 to 1:0, followed by methanol. The added potassium carbonate (40 mg, 0.29 mmol). The reaction appropriate fractions were combined and concentrated to give mixture was then heated at 60° C. overnight. The reaction 65 mixture was concentrated in vacuo and the residue was par the titled compound (200 mg). titioned between dichloromethane (10 ml) and water (10 ml). Experimental MH 580.9; expected 581.0 US 7,687,533 B2 93 94 Similarly prepared was: purified by column chromatography (silica, 50 g) with gradi ent elution, cyclohexane:dichloromethane 1:0 to 0:1, fol Preparation 46 lowed by dichloromethane:methanol 95:5). The appropriate fractions were combined and concentrated to give the titled N-(3-cyano-1-2,6-dichloro-4-(trifluoromethyl)phe- 5 compound (240 mg). nyl-5-(dimethylaminomethyleneamino)-1H H-NMR (CDC13): 2.79-2.85 (3H), 3.02-3.08 (3H), 3.45 pyrazol-4-yl)-N,N-bis-(1,1,1-trifluoromethane)sul 3.51 (3H), 7.69-7.74 (2H), 8.02-8.07 (1H) phonamide, from Preparation 51 (800 mg, 2.05 mmol) and trifluoromethaneSulphonic anhydride Preparation 50 (860 ul, 2.05 mol) to give the title compound (1.3 g) 10 N'-3-cyano-1-2,6-dichloro-4-(trifluoromethyl)phe nyl-4-(1,1-dioxidoisothiazolidin-2-yl)-1H-pyrazol Experimental MH" 655.3; expected 655.0 5-yl-N,N-dimethylimidoformamide Preparation 47 A mixture of Preparation 76 (127 mg, 0.24 mmol) and N-3-cyano-1-2,6-dichloro-4-pentafluorothiophe 15 potassium carbonate (36 mg, 0.26 mmol) in N,N-dimethyl nyl-5-iodo-1H-pyrazol-4-yl)-N-(2.2.2-trifluoroet formamide (2 ml) was stirred at room temperature for 2 h. To hyl)methanesulfonamide the reaction mixture was added ethyl acetate (10 ml) and water (10 ml) and the two layers were separated. The aqueous To a mixture of Example 32 (447 mg, 0.81 mmol) and layer was extracted with ethyl acetate (x2) and the combined iodine (881 mg, 3.47 mmol) in acetonitrile (10 ml) was added organic phases were dried (MgSO4) and concentrated in isoamylnitrite (0.13 ml, 0.97 mmol). The reaction mixture vacuo to give the titled compound (110 mg). was then heated at 50° C. for 1 h. To the reaction mixture was Experimental MH 495.2: expected 495.0 added Saturated aqueous Sodium thiosulphate solution (30 Preparation 51 ml) and the mixture was extracted with ethyl acetate (2x20 ml). The combined extracts were washed with brine (50 ml), 25 dried (MgSO) and concentrated in vacuo. The residue was N'-(4-amino-3-cyano-1-2,6-dichloro-4-(trifluorom dissolved in acetonitrile (2 ml) and purified by automated ethyl)phenyl)-1H-pyrazol-5-yl-N,N-dimethylimido preparative liquid chromatography (Gilson system, 150 formamide mmx50 mm Phenomonex LUNA C18(2) 10 um column) using an acetonitrile:water gradient 55:45 to 95:5). The 30 To a solution of Preparation 77 (423 mg, 0.79 mmol) in appropriate fractions were concentrated in vacuo to give the tetrahydrofuran (15 ml) was added tetrabutylammonium titled compound (283 mg). fluoride (1M intetrahydrofuran, 3.2 ml, 3.2 mmol). The reac H-NMR (CDC13): 3.24-3.28 (3H), 4.07-4.20 (1H), 4.35 tion mixture was then heated at 50° C. for 1 h. The reaction 449 (1H), 7.90-7.93 (2H) mixture was concentrated in vacuo and the residue partitioned 35 between dichloromethane (20 ml) and water (20 ml). The Preparation 48 organic phase was separated, dried (MgSO) and concen trated in vacuo. The residue was purified by column chroma N-3-cyano-1-2,6-dichloro-4-pentafluorothiophe tography with gradient elution, ethyl acetate:hexane 1:2 to nyl-5-(2-oxoethyl)amino)-1H-pyrazol-4-yl)-N-(2, 4:1. The appropriate fractions were combined and concen trated to give the titled compound (220 mg, 71%). 2.2-trifluoroethyl)methanesulfonamide 40 Experimental MH 391.2: expected 391.1 To a solution of Preparation 75 (560 mg. 0.94 mmol) in Alternative Synthesis aqueous acetone (10%, 16.6 ml) was added osmium tetroxide A solution of Preparation 61 (1.20g, 2.85 mmol) in metha solution (2.5%, 33 umol). To the mixture was added sodium nol (25 ml) was placed under a hydrogen atmosphere (15 psi), periodate (880 mg, 2.07 mmol) and the reaction mixture was 45 with platinum (5% on charcoal), at room temperature for 3 h. stirred at room temperature overnight. The reaction mixture The reaction mixture was filtered through a pad of Arbocel(R), was filtered and the filtrate was concentrated in vacuo. The washing through with dichloromethane/methanol and the fil residue was partitioned between dichloromethane and water trate was concentrated in vacuo. The residue was purified and the organic layer was separated, dried (MgSO4) and using an IsoluteTM cartridge (silica, 25g), eluting with dichlo concentrated in vacuo to give the titled compound (134 mg). romethane/methanol 99:1. The appropriate fractions were 'H-NMR (CDC13): 3.17-3.20 (3H), 4.20-4.29 (2H), 4.32 combined and concentrated to give the titled compound (1.0 4.46 (2H), 4.76-4.81 (1H), 7.91-7.93 (2H), 9.58-9.59 (1H) g). Experimental MH 391.1; expected 391.1 Preparation 49 Preparation 52 N-(3-cyano-1-2,6-dichloro-4-(trifluoromethyl)phe- 55 nyl-5-(dimethylamino)methylenelamino)-1H 1-(trifluoromethyl)cyclopropyl)methyl pyrazol-4-yl)-1,1,1-trifluoro-N-methylmethane 4-methylbenzenesulfonate Sulfonamide To a solution of 1-(trifluoromethyl)cyclopropyl)methanol To a solution of Preparation 46 (1.3 g, 1.98 mmol) in 60 (J. Fluorine Chem., 2001, 109, 2,95, 8.18 g, 58.4 mmol) in tetrahydrofuran (11 ml), at 0°C., was added potassium car dichloromethane (50 ml), at 0°C., was added triethylamine bonate (685 mg, 4.96 mmol) in methanol (11 ml) and water (3 (50 ml), 4-dimethylaminopyridine (713 mg, 5.84 mmol) and drops). The reaction mixture was then stirred at room tem p-toluenesulphonyl chloride (11.1 g, 58.4 mmol). The reac perature for 2 h. The reaction mixture was concentrated in tion mixture was allowed to warm to room temperature and vacuo and to the residue was added dichloromethane. The 65 stirred overnight. The reaction mixture was concentrated in solution was washed with hydrochloric acid (1N) and brine, vacuo and the residue was partitioned between diethyl ether dried (MgSO) and concentrated in vacuo. The residue was (250 ml) and hydrochloric acid (0.5M, 100 ml). The two US 7,687,533 B2 95 96 layers were separated and the aqueous phase was extracted Similarly prepared was: with diethyl ether (100 ml). The combined organic phases were washed with Saturated aqueous sodium hydrogencar Preparation 54 bonate solution (50 ml) and brine (50 ml), dried (MgSO) and concentrated in vacuo. The residue was purified using a BiotageTM Flash 40 system with gradient elution, diethyl 5 2-(trimethylsilyl)ethyl 1-2,6-dichloro-4-pentafluo ether:cyclohexane 5:95 to 20:80. The appropriate fractions rothiophenyl-5-(dimethylamino)methylene were combined and concentrated to give the titled compound amino-3-(trifluoromethyl)-1H-pyrazol-4-ylcarbam (11.8 g). ate H-NMR (CDC13): 0.81-0.89 (2H), 1.09-1.16 (2H), 2.44 2.48 (3H), 4.09-4.12 (2H), 7.33-7.39 (2H), 7.77-7.82 (2H) 10 from the compound of Preparation 80 (1.22 g, 2.35 mmol), Preparation 53 diphenylphosphoryl azide (0.56 ml, 2.59 mmol) and 2-silyle thanol (0.37 ml, 2.59 mmol) to give the title compound (0.91 2-(trimethylsilyl)ethyl 3-cyano-1-2,6-dichloro-4- g). pentafluorothiophenyl-5-(dimethylamino)methyl enelamino)-1H-pyrazol-4-ylcarbamate 15 Experimental MH 636.0; expected 636.1 To a solution of Preparation 78 (6.7g, 14.0 mmol), triethy Preparation 55 lamine (2.14 ml, 15.4 mmol) and 2-trimethylsilylethanol (2.21 ml, 15.4 mmol) in 1,4-dioxane (100 ml) was added N'-3-cyano-1-2,6-dichloro-4-pentafluorothiophe diphenylphosphoryl azide (3.34 ml, 15.4 mmol). The reaction 2O nyl-4-nitro-1H-pyrazol-5-yl-N,N-dimethylimido mixture was heated at reflux for 3 hand then stirred overnight formamide at room temperature. To the reaction mixture was added ethyl acetate (200 ml) and the mixture was washed with hydrochlo To a solution of nitronium tetrafluoroborate (470 mg, 3.5 ric acid (1M, 2x250 ml). The aqueous phase was re-extracted mmol) in acetonitrile (15 ml) was added Preparation 81 (1.0 with ethyl acetate (200 ml) and the organic phases were 25 g, 2.9 mmol). The reaction mixture was then stirred at room combined, washed with brine (200 ml), dried (NaSO) and temperature for 2 h. The reaction mixture was diluted with concentrated in vacuo. The residue was purified by column ethyl acetate, washed with water and saturated brine solution, chromatography (silica, 300 g) with gradient elution, metha dried (MgSO) and concentrated in vacuo to give the titled nol:dichloromethane 0:100 to 5:95. The appropriate frac compound (960 mg). tions were combined and concentrated to give the titled com 30 pound (9.0 g). Experimental MH 478.8; expected 479.0 Experimental MH 593.0; expected 593.1 Similarly prepared were:

O V R2a NN O ( \ YN R3a C R1b

R1a MS (ES): M/Z From MH+] prep R1a. R1b. R2a R3a. prep (expected mass) 56 SFs Cl cyclopropyl N 21N -CH3 82 494.0; (494.0) N N CH3

57 H 83 454.0; (454.0) 58 H CN 84 59 C OMe 93 : 60 pyridin-4- 94 514.9; (515.0) ylmethyl)amino 61 CF nan -CH3 85 :::::: N CH3

62 OCF 87 437.0; (437.0) US 7,687,533 B2 97 98

-continued O R2a \ No. ( \ YN R3a C R1b

R1a MS (ES): M/Z From MH+] prep R1a. R1b. R2a R3a. prep (expected mass) 63 SCF. " 88 453.0; (453.0) 64 OCHF. " 89 419.0; (419.0) * H-NMR (CDC13): 4.24-4.33 (3H), 7.89-7.96 (2H) ** H-NMR (DMSO):273-277 (3H), 3.06-3.09 (3H), 8.20-8.27 (2H), 8.53-8.56 (1H)

Preparation 65 25 -continued 1-2,6-dichloro-4-(trifluoromethyl)phenyl-5-(me- N O thylamino)-4-nitro-1H-pyrazole-3-carbonitrile \ V 30 N A mixture of 5-bromo-1-2,6-dichloro-4-(trifluoromethyl) f O phenyl]-4-nitro-1H-pyrazole-3-carbonitrile (EP 2951 18 A1, N \ R12 50 mg, 0.12 mmol) and methylamine (2M in tetrahydrofuran, YN N1 1.0 mmol. 2.0 mmol) was heated at 55° C. for 2.5 h. To the 35 Yi reaction mixture was added water (5 ml), followed by ethyl C C acetate (5 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (3x5 ml). The com bined organic phases were dried (MgSO) and concentrated in vacuo to give the titled compound (42 mg). 40 n- F 'H-NMR (CDC13): 2.65-2.69 (3H), 7.29-7.37 (1H), 7.76- F1 NF 7.80 (2H) F Similarly prepared from Preparation 92 were: MS (ES): M/Z MH+] Prep R12 R13 (expected mass) 45 69 H 2-piperidin-1-ylethyl 535.0; (535.0) N O 70 Me 2-(dimethylamino)ethyl 509.0; (5090) \ \N W 50 Preparation 71 N \ R12 YN N1 N'-4-amino-1-2,6-dichloro-4-pentafluorothiophe Y. 13 nyl-3-(trifluoromethyl)-1H-pyrazol-5-yl-N,N-dim C C ethylimidoformamide 55 To a solution of Preparation 54 (0.91 g, 1.43 mmol) in F F tetrahydrofuran (27 ml) was added tetrabutylammonium N1 fluoride (5.7 ml, 5.7 mmol), via syringe. The reaction mixture 1 N was then heated at 50° C. for 1 h. The reaction mixture was 60 concentrated in vacuo and the residue was partitioned between dichloromethane and water. The organic phase was MS (ES): M/Z MH+] then separated, dried (MgSO) and concentrated in vacuo. Prep R12 R13 (expected mass) The residue was purified by column chromatography with 66 2-morpholin-4-ylethyl 537.0; (537.0) gradient elution, ethyl acetate:cyclohexane 1:4 to 2:3. The 67 2-(dimethylamino)ethyl 495.0; (495.0) 65 appropriate fractions were combined and concentrated to give 68 2-pyrrollidin-1-ylethyl 521.1; (521.0) the titled compound (0.64 g). Experimental MH" 491.9; expected 492.0 US 7,687,533 B2 99 100 Preparation 72 Preparation 76 N'-(4-amino-3-cyano-1-2,6-dichloro-4-(trifluo 3-chloro-N-(3-cyano-1-2,6-dichloro-4-(trifluorom romethoxy)phenyl)-1H-pyrazol-5-yl-N,N-dimeth ethyl)phenyl-5-(dimethylamino)methylene ylimidoformamide amino)-1H-pyrazol-4-yl)propane-1-sulfonamide To a solution of Preparation 51 (100 mg, 0.26 mmol) in To a solution of Preparation 62 (750 mg, 1.91 mmol) in pyridine (2 ml), under nitrogen, was added 3-chloropropane methanol was added platinum (10 wt.% on carbon) and the sulphonyl chloride (34 ul, 0.28 mmol) and the reaction mix mixture was placed in a hydrogen atmosphere (50 psi) for 8 h. 10 ture was stirred overnight at room temperature. To the reac tion mixture was added ethyl acetate (10 ml) and water (10 The reaction mixture was filtered through Arbocel(R) and the ml) and the two layers were separated. The aqueous layer was filtrate was concentrated in vacuo. The residue was parti extracted with ethyl acetate (x2) and the combined organic tioned between dichloromethane and water and the organic phases were washed with hydrochloric acid (1M), water and phase was separated, dried and concentrated in vacuo to give brine, dried (MgSO) and concentrated in vacuo to give the the titled compound (650 mg). 15 titled compound (127 mg). Experimental MH" 407.0; expected 407.0 Experimental MH 529.1; expected 529.0 Preparation 77 Preparation 73 2-(trimethylsilyl)ethyl 3-cyano-1-2,6-dichloro-4- N'-(4-amino-3-cyano-1-(2,6-dichloro-4-(difluo (trifluoromethyl)phenyl-5-(dimethylamino)meth romethoxy)phenyl)-1H-pyrazol-5-yl-N,N-dimeth ylenelamino)-1H-pyrazol-4-ylcarbamate ylimidoformamide To a solution of Preparation 79 (420 mg, 1.0 mmol) in 25 1,4-dioxane (6 ml) was added triethylamine (0.15 ml, 1.1 from the compound of Preparation 64 (850 mg, 2.03 mmol) mmol) and 2-(trimethylsilyl)ethanol (0.16 ml, 1.1 mmol), to give the title compound (580 mg). followed by the dropwise addition of diphenylphosphoryl Experimental MH 389.0; expected 389.0 azide (0.24 ml, 1.1 mmol). The reaction mixture was then heated at reflux overnight. The reaction mixture was concen Preparation 74 30 trated in vacuo and the residue partitioned between ethyl acetate (20 ml) and hydrochloric acid (1N, 20 ml). The organic phase was separated, dried (MgSO4) and concen N-(2-bromoethyl)-N-(3-cyano-1-2,6-dichloro-4- trated in vacuo. The residue was purified by column chroma pentafluorothiophenyl-5-(dimethylamino)methyl tography with gradient elution, ethyl acetate:hexane 1:2 to enelamino)-1H-pyrazol-4-yl)methanesulfonamide 2:1. The appropriate fractions were combined and concen 35 trated to give the titled compound (423 mg). To a mixture of Preparation 3 (1.66 mg, 0.32 mmol) and Experimental MH 535.4; expected 535.1 1,2-dibromoethane (0.14 ml, 1.58 mmol) in acetonitrile (12 Preparation 78 ml) was added potassium carbonate (52 mg, 0.38 mmol). The reaction mixture was then heated at 70° C. overnight. The 40 3-cyano-1-2,6-dichloro-4-pentafluorothiophenyl-5- reaction mixture was concentrated in vacuo and the residue {(dimethylamino)methylenelamino)-1H-pyrazole was partitioned between dichloromethane (30 ml) and water 4-carboxylic acid (30 ml). The organic phase was separated, dried (MgSO4) and To a solution of Preparation 95 (8.0 g, 16.25 mmol) in concentrated in vacuo to give the titled compound (154 mg). 45 anhydrous pyridine (80 ml) was added lithium iodide (10.9 g, Experimental MH 632.9; expected 632.9 81.25 mmol). The reaction mixture was then heated at reflux, under nitrogen, overnight. The reaction mixture was concen Preparation 75 trated in vacuo and the residue was partitioned between ethyl acetate (200 ml) and hydrochloric acid (2N, 200 ml). The 50 organic layer was separated, washed with hydrochloric acid N-5-(allylamino)-3-cyano-1-(2,6-dichloro-4-pen (2N, 2x200 ml) and brine (200 ml), dried (NaSO) and tafluorothiophenyl)-1H-pyrazol-4-yl)-N-(2,2,2-trif. concentrated in vacuo. The residue was purified by column luoroethyl)methanesulfonamide chromatography (silica, 300 g) with gradient elution, metha nol:dichloromethane (0.5:95.5 to 10:90. The appropriate fractions were combined and concentrated to give the titled To a solution of Example 32 (3.0 g, 5.4 mmol) in tetrahy 55 compound (6.7 g). drofuran (27 ml), at 0°C., was added sodium hydride (0.24g, Experimental MH 477.8; expected 478.0 5.94 mmol). The mixture was allowed to warm to room tem Similarly prepared were: perature and allyl bromide (2.3 ml, 27.0 mmol) was added. The reaction mixture was then stirred at room temperature for Preparation 79 2 days. To the reaction mixture was added water and ethyl 60 acetate. The organic layer was separated, dried (MgSO4) and 3-cyano-1-2,6-dichloro-4-(trifluoromethyl)phenyl concentrated in vacuo. The residue was purified by column 5-(dimethylamino)methylenelamino)-1H-pyra chromatography with gradient elution, ethyl acetate:cyclo Zole-4-carboxylic acid hexane 5:95 to 1:5. The appropriate fractions were com 65 from the compound of Preparation 90 (2.0 g, 4.61 mmol) to bined and concentrated to give the titled compound (1.34g). give the titled compound (1.5 g). Experimental MH" 594.1; expected 594.0 Experimental MH" 420.2: expected 420.0 US 7,687,533 B2 101 102 Preparation 80 -continued 1-2,6-dichloro-4-pentafluorothiophenyl-5-(dim ethylamino)methylenelamino-3-(trifluoromethyl)- R2a R3a 1H-pyrazole-4-carboxylic acid 2 CH from the compound of Preparation 91 (2.12g, 4.1 mmol) to 1. give the titled compound (1.22 g). N N r R C CH Experimental MH" 521.0; expected 521.0 10 Preparation 81

N'-3-cyano-1-(2,6-dichloro-4-pentafluorothiophe R1a nyl)-1H-pyrazol-5-yl-N,N-dimethylimidoforma 15 mide From MS (ES): M/Z MH--l Prep R1a. R1b R2a R3a. prep (expected mass) To a solution of Preparation 86 (2.2g, 3.9 mmol) in dry 90 CF - CO-Me 107 434.2; (434.1) tetrahydrofuran (30 ml), at -30°C., was added isopropylmag 91 SFs CF 108 535.0; (535.0) nesium chloride (2M in N,N-dimethylformamide, 2.2 ml. 4.4 *5-amino-1-2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbo mmol). The reaction mixture was then allowed to warm to nitrile (WO9839302 A1) room temperature over 1 h. To the reaction mixture was added *5-amino-1-2,6-dichloro-4-pentafluorothiophenyl]-4-iodo-1H-pyrazole-3- carbonitrile (WO9824761 A1, WO 98.04530 A1) saturated aqueous ammonium chloride solution (10 ml) and ***H-NMR (DMSO): 2.63-2.65 (3H), 2.96-2.98 (3H), 6.61-6.63 (1H), ethyl acetate (excess). The organic layer was separated, 8.13-8.15 (1H), 8.16-8.18 (2H) washed with saturated brine solution, dried (MgSO) and 25 ****H-NMR (CDC13): 2.77-2.81 (3H), 3.02-3.05 (3H), 7.78-7.81 (2H), concentrated in vacuo to give the titled compound (1.6 g). 8.21-8.24 (1H) Experimental MH" 433.8; expected 434.0 Preparation 92 Preparation 82 30 5-bromo-1-2,6-dichloro-4-pentafluorothiophenyl N'-3-cyclopropyl-1-(2,6-dichloro-4-pentafluo 4-nitro-1H-pyrazole-3-carbonitrile rothiophenyl)-1H-pyrazol-5-yl)-N,N-dimethylimido formamide To a solution of Preparation 98 (5.0 g, 12.0 mmol) and bromoform (16 ml, 18.3 mmol) in acetonitrile (50 ml) was A solution of Preparation 96 (3.3 g, 8.40 mmol) in N.N- 35 added dropwise tert-butyl nitrite (8 ml, 67.3 mmol). The dimethylformamide dimethyl acetal (15 ml) was heated at reaction mixture was then heated at 55° C. for 16 h. The reflux for 2h. The reaction mixture was concentrated in vacuo reaction mixture was concentrated in vacuo and the residue and the residue was absorbed onto silica and purified by was re-crystallised from cyclohexane/ethyl acetate 20:1 to column chromatography, eluting with cyclohexane/ethyl give the titled compound (3.1 g). acetate 4:1. The appropriate fractions were combined and 40 'H-NMR (CDC13): 7.92-7.97 (2H) concentrated to give the titled compound (3.7g). Experimental MH" 449.0; expected 449.0 Preparation 93 Similarly prepared were: 1-2,6-dichloro-4-pentafluorothiophenyl-5-meth 45 oxy-1H-pyrazole-3-carbonitrile To a solution of Preparation 100 (650 mg, 1.71 mmol) in acetonitrile (15 ml) was added potassium carbonate (708 mg, 5.13 mmol) and methyl iodide (0.32 ml, 5.14 mmol) and the reaction mixture was heated at 40°C. overnight. The reaction 24n. -CH3 50 mixture was concentrated in vacuo and the residue was par titioned between water (30 ml) and ethyl acetate (30 ml). The R C CH two layers were separated and the organic layer was washed with brine (30 ml), dried (MgSO) and concentrated in vacuo. The residue was purified by column chromatography with 55 gradient elution, hexane:ethyl acetate 5:1 to 3:1. The appro priate fractions were combined and concentrated to give the titled compound (474 mg). Experimental MH 393.9; expected 394.0 From MS (ES): M/Z MH--l Prep R1a. R1b R2a R3a. prep (expected mass) 60 Preparation 94 83 SFs C H H 97 409.0; (409.01) 84 H CN 99 400.0; (400.0) 1-2,6-dichloro-4-pentafluorothiophenyl-5-(pyri 85 CF C : ::::::::: din-4-ylmethyl)amino)-1H-pyrazole-3-carbonitrile 86 SFs I :::::: :::::::::::: 87 OCF H 104 392.0; is (392.0) 88 SCF 103 408.0; (408.0) 65 To a mixture of 5-amino-1-2,6-dichloro-4-pentafluo 89 OCHF, 106 374.0: (3740) rothiophenyl)-1H-pyrazole-3-carbonitrile (WO9306089 A1, 1.00 g, 2.63 mmol) and p-toluenesulphonic acid (5 mg) in US 7,687,533 B2 103 104 toluene (20 ml) was added 4-pyridinecarboxaldehyde (0.35 resulting precipitate was collected by filtration, washed with ml, 3.68 mmol). The reaction mixture was then heated at water and dried to give the titled compound (4.2 g). reflux for 1.5h. The reaction mixture was partitioned between Experimental MH 354.0; expected 354.0 ethyl acetate and water and the organic layer was separated, washed with water, dried (MgSO) and concentrated in Preparation 98 vacuo. To a solution of the residue in methanol (48 ml) was added sodium borohydride (48 mg, 1.26 mmol) and the mix 5-amino-1-2,6-dichloro-4-pentafluorothiophenyl-4- ture was stirred at room temperature for 2 h. The reaction nitro-1H-pyrazole-3-carbonitrile mixture was concentrated in vacuo and the residue was par titioned between ethyl acetate and water. The organic layer 10 To a solution of Preparation 55 (10.0 g. 20.9 mmol) in was separated, dried (MgSO4) and concentrated in vacuo to dioxane (160 ml) was added methanol (20 ml) and hydrochlo give the titled compound (1.26 g). ric acid (10%, 20 ml). The reaction mixture was heated at 90° Experimental MH 470.0; expected 470.0 C. for 56 hand additional hydrochloric acid (concentrated, 2 ml) was added. The reaction mixture was then heated at 90° C. Preparation 95 for a further 15 h. To the reaction mixture was added aqueous 15 Sodium hydrogencarbonate solution (50 ml) and ethyl acetate methyl 3-cyano-1-2,6-dichloro-4-pentafluo (100 ml). The two layers were separated and the aqueous rothiophenyl-5-(dimethylamino)methylene layer was extracted with ethyl acetate (2x100 ml). The com amino)-1H-pyrazole-4-carboxylate bined organic phases were washed with brine, dried (MgSO) and concentrated in vacuo. The residue was triturated with A mixture of Preparation 86 (50.0 g, 89.3 mmol), triethy dichloromethane to give the titled compound (6.6 g). lamine (24.9 ml, 178.6 mmol) and 1,1'-bis(diphenylphos Experimental MH" 424.0; expected 424.0 phino) ferrocenedichloropalladium(II).dichloromethane (2.0 g) in methanol (500 ml) was heated at 65° C. under Preparation 99 carbon monoxide (150 psi) for 8 h. To the reaction mixture 25 was added water (21) and the mixture was stirred for 30 min. 5-amino-1-(2-chloro-4-pentafluorothio-phenyl)-1H The precipitate was collected by filtration and air-dried to pyrazole-3-carbonitrile give the titled compound (43.3 g). 'H-NMR (DMSO): 2.67-2.70 (3H), 3.00-3.03 (3H), 3.72 To sulphuric acid (concentrated, 1.75 ml) was added care 3.77 (3H), 8.36-8.38 (1H), 8.41-8.43 (2H) fully sodium nitrite (432 mg, 6.26 mmol), followed by glacial 30 acetic acid (2.5 ml). The solution was stirred at 10°C. for 1 h, Preparation 96 before Preparation 105 (1.44 g. 5.69 mmol) in glacial acetic acid (1 ml) was added dropwise. The mixture was heated at 50° C. for 1 h, allowed to cool to room temperature, and then 3-cyclopropyl-1-2,6-dichloro-4-pentafluorothiophe added dropwise to ethyl 2,3-dicyanopropanoate (Hainzl, D.; nyl)-1H-pyrazol-5-amine 35 Cole, L. M.: Casida, J. E. Chemical Research in Toxicology (1998), 11(12), 1529-1535,864 mg, 5.69 mmol) in acetic acid To a solution of Preparation 101 (1.55 g, 14.2 mmol) in (1 ml) and ice water (2 ml). The reaction mixture was then 2-propanol (30 ml) was added Preparation 102 (4.28 g. 14.2 stirred at room temperature for 45 min. The reaction mixture mmol). The reaction mixture was heated at reflux for 16 h. was poured into water (200 ml) and the mixture was extracted The mixture was cooled to room temperature and concen 40 with dichloromethane (100 ml). To the organic extract was trated sulphuric acid (0.1 ml) was added, followed by acetic added aqueous ammonium hydroxide solution (880, 25 ml) acid (0.6 ml). The reaction mixture was then heated at reflux and water (25 ml) and the mixture was stirred at room tem for a further 4 h. The reaction mixture was concentrated in perature overnight. The reaction mixture was partitioned vacuo and to the residue was added water and saturated aque between dichloromethane (100 ml) and water (100 ml) and ous sodium hydrogencarbonate solution (30 ml). The mixture the organic phase was separated, dried (MgSO4) and concen was extracted with ethyl acetate and the combined extracts 45 trated in vacuo to give the titled compound (700 mg). were dried (MgSO) and concentrated in vacuo. The residue Experimental MH 345.1; expected 345.0 was absorbed onto silica and purified by column chromatog raphy with gradient elution, cyclohexane:ethyl acetate 4:1 to Preparation 100 2:1. The appropriate fractions were combined and concen trated to give the titled compound (3.4 g). 50 1-2,6-dichloro-4-pentafluorothiophenyl-5-hydroxy 1H-pyrazole-3-carbonitrile Preparation 97 1-2,6-dichloro-4-pentafluorothiophenyl)-1H-pyra Sodium nitrite (1.32 g, 19.1 mmol) was added carefully to 55 Sulphuric acid (concentrated, 6.8 ml), whilst cooling the solu Zol-5-amine tion to 0°C. The solution was heated to 60° C. for 30 min, allowed to cool and then diluted with acetic acid (12 ml). To To a solution of Preparation 102 (4.0 g, 13.2 mmol) and the solution was added 2,6-dichloro-4-pentafluorothiopheny ethylenediaminetetraacetic acid disodium salt (catalytic lamine (WO9421606 A1, 5.0 mg, 17.4 mmol) in acetic acid amount) in methanol (40 ml), heated at reflux, was added (11 ml) and the reaction mixture was heated at 55° C. for 1 h. 2-chloroacrylonitrile (3.2 ml, 39.6 mmol) dropwise. The 60 To a solution of dimethyl 2-cyanosuccinate (Hall, H. K., Jr.; reaction mixture was heated at reflux overnight, before addi Ykman, P.J. Am. Chem. Soc. (1975),97(4),800-807, 3.09 g, tion of Sulphuric acid (concentrated, 1.2 ml, 21.1 mmol). 18.1 mmol) in acetic acid (24 ml) and water (36 ml) was After heating at reflux for a further 6 h, anhydrous sodium added dropwise the solution of the diazonium salt, followed carbonate (4.2 g, 39.6 mmol) was added and the reaction by Sodium acetate (24.2 g) in water (42 ml). The reaction mixture was stirred overnight at room temperature. The reac 65 mixture was then stirred at room temperature for 30 min. The tion mixture was concentrated in vacuo and to the residue was reaction mixture was poured into ice/water (200 ml) and the added water (150ml). The mixture was stirred for 60hand the mixture was extracted with dichloromethane (4x60 ml). The US 7,687,533 B2 105 106 combined extracts were then washed with ammonium mixture was then heated at 50° C. for 1 h and cooled to room hydroxide (48 ml), dried and concentrated in vacuo. To a temperature. To a solution of ethyl 2,3-dicyanopropanoate solution of sodium methoxide (25 wt.%, 11.5 ml, 50.1 mmol) (Hainzl, D.; Cole, L. M.: Casida, J. E. Chemical Research in in methanol (450 ml) was added dropwise a solution of the Toxicology (1998), 11(12), 1529-1535, 500 mg, 3.29 mmol) residue in methanol (100 ml). The reaction mixture was then in acetic acid (5 ml) was added ice water (5 ml), followed by stirred at room temperature for 2 h. The reaction mixture was the solution of the diazonium salt, added dropwise at 0°C. concentrated in vacuo and to the residue was added water. After complete addition, ammonium hydroxide (6 ml) was This solution was adjusted to pH1 by addition of hydrochlo added and the reaction mixture was stirred overnight at room ric acid (4N) and the mixture was extracted with dichlo temperature. The reaction mixture was filtered through romethane (3x100 ml). The combined extracts were dried Arbocel(R) and the filtrate was concentrated in vacuo. The (MgSO) and concentrated in vacuo. The residue was purified 10 residue was partitioned between dichloromethane and water by column chromatography, eluting with hexane/ethyl and the organic phase was separated, dried (NaSO) and acetate 3:1. The appropriate fractions were combined and concentrated in vacuo to give the titled compound (1.0 g). concentrated to give the titled compound (4.5 g). Experimental MH 353.0; expected 353.0 Experimental MH379.8; expected 380.0 15 Preparation 104 Preparation 101 5-amino-1-2,6-dichloro-4-(trifluoromethoxy)phe 3-cyclopropyl-3-oxopropanenitrile nyl)-1H-pyrazole-3-carbonitrile To a solution of cyanoacetic acid (4.25 g, 50.0 mmol) in To sulphuric acid (18M, 54 ml) was added sodium nitrite tetrahydrofuran (80 ml) and dichloromethane (40 ml), at 0° (13.9 g, 201.2 mmol) and the solution was stirred at 15°C. for C., was added isopropylmagnesium chloride (2M in tetrahy 1 h. To the solution was added acetic acid (200 ml), followed drofuran, 50 ml, 100 mmol). In a separate reaction vessel, by 2,6-dichloro-4-(trifluoromethoxy)aniline (45.0 g, 182.9 1,1-carbonyldiimidazole (4.05 g, 25.0 mmol) was added to mmol) in acetic acid (90 ml), ensuring the temperature of the cyclopropylcarboxylic acid (2.15g, 25.0 mmol) in tetrahy 25 solution did not rise above 20° C. After addition was com drofuran (80 ml), at 0°C. The two mixtures were combined plete, the mixture was heated at 50° C. for 1 h, cooled to room with additional tetrahydrofuran (60 ml) and the reaction mix temperature and added dropwise to a solution of ethyl 2.3- ture was stirred at room temperature for 60 h. To the reaction dicyanopropanoate (Hainzl, D.; Cole, L. M.: Casida, J. E. mixture was added hydrochloric acid (2N), at 0°C., and the Chemical Research in Toxicology (1998), 11(12), 1529 mixture was stirred for 1 h. The mixture was concentrated in 30 1535, 27.8 g., 182.9 mmol) in acetic acid (115 ml) and ice cold vacuo and to the residue was added water. After extracting water (145 ml). The reaction mixture was then stirred over with diethyl ether (2x100 ml), the combined extracts were night at room temperature. To the reaction mixture was added washed with Saturated aqueous sodium hydrogencarbonate dichloromethane (500 ml) and the mixture was stirred for 10 solution (60 ml) and water (60 ml), dried (MgSO) and con min. The two phases were separated and the organic phase centrated in vacuo to give the titled compound (1.5 g). 35 was washed with water (200 ml) and ammonia (0.88, 400 ml) 'H-NMR (CDC13): 1.02-1.08 (2H), 1.13-1.18 (2H), 2.03 was added dropwise, maintaining the temperature of the mix 2.09 (1H), 3.57-3.60 (2H) ture below 10°C. This mixture was stirred overnight at room temperature and the organic phase was separated and concen Preparation 102 trated in vacuo. The residue was re-crystallised from toluene/ pentane 2:1 to give the titled compound (22.4 g). 2,6-dichloro-4-pentafluorothiophenylhydrazine 40 Experimental MH 337.0; expected 337.0 To a mixture of Sulphuric acid (concentrated, 24 ml) and Preparation 105 sodium nitrite (6.0 g, 87.0 mmol) at 10°C., was added 2,6- dichloro-4-pentafluorothiophenylamine (WO 9421606 A1, 2-chloro-4-pentafluorothio-phenylamine 23.5g, 82.0 mmol) in glacial acetic acid (92 ml) over 20 min. 45 The reaction mixture was stirred at 25°C. for 20 minand then To a solution of 4-(pentafluorothio)phenylamine (WO heated at 60°C. for 1 h. The reaction mixture was cooled to 5° 9421606A1, 1.29 g, 5.89 mmol) in acetonitrile (15 ml) at 45° C. and tin(II) chloride (65.6 g., 0.35 mol) in hydrochloric acid C. was added N-chlorosuccinimide (786 mg, 5.89 mmol). (concentrated, 56 ml) was added. After stirring for 30 min, the The reaction mixture was then stirred at 45° C. for 3 h. The precipitate was collected by filtration and added to ammonia 50 reaction mixture was concentrated in vacuo and the residue (400 ml) and ice (100 ml). This mixture was extracted with was partitioned between dichloromethane (20 ml) and water diethyl ether (5x200 ml) and the combined extracts were (20 ml). The organic phase was separated, dried and concen dried (MgSO) and concentrated in vacuo to give the titled trated in vacuo to give the titled compound (1.44 g). compound (19.3 g). Experimental MH' 254.1; expected 254.0 H-NMR (CDC13): 3.61-3.82 (2H), 5.75-5.91 (1H), 7.60 55 7.65 (2H) Preparation 106 Preparation 103 5-amino-1-2,6-dichloro-4-(difluoromethoxy)phe nyl)-1H-pyrazole-3-carbonitrile 5-amino-1-(2,6-dichloro-4-(trifluoromethyl)thiol 60 phenyl)-1H-pyrazole-3-carbonitrile To sulphuric acid (concentrated, 21 ml), at 15° C., was added sodium nitrite (4.8 g. 69.6 mmol). After stirring for 1 h, Sodium nitrite (224 mg. 3.25 mmol) was added carefully to glacial acetic acid (17.3 ml) was added, followed by Prepa Sulphuric acid (concentrated, 1 ml), ensuring that the tem ration 110 (13.8 g. 60.3 mmol) in acetic acid (33.8 ml), added perature did not rise above 30° C. After stirring at 15° C. for 65 dropwise, keeping the temperature of the mixture below 25° 1 h, acetic acid (2 ml) was added, followed by Preparation 109 C. The solution was heated at 50° C. for 1 h, cooled and added (850 mg, 3.24 mmol) in acetic acid (3 ml). The reaction dropwise to a mixture of ethyl 2,3-dicyanopropanoate US 7,687,533 B2 107 108 (Hainzl, D.; Cole, L. M.: Casida, J. E. Chemical Research in extracts were dried (MgSO) and concentrated in vacuo to Toxicology (1998), 11(12), 1529-1535, 10.6 g. 69.6 mmol), give the titled compound (1.0 g). acetic acid (42.8 ml) and ice/water (55 ml), at 0° C. The reaction mixture was then stirred at room temperature over Preparation 110 night. To the reaction mixture was added dichloromethane (300 ml) and the mixture was stirred. The two layers were 2,6-dichloro-4-(difluoromethoxy)phenylamine separated and the organic layer was washed with water. To the organic layer was added ammonium hydroxide (concen To a solution of 4-(difluoromethoxy)methylaniline (15.0 trated, 125 ml) and ice and the mixture was stirred at 5°C. for g, 94.3 mmol) in acetonitrile (150 ml) was added N-chloro 4 h. The organic layer was again separated and stirred over 10 Succinimide (25.2g, 18.9 mmol) and the reaction mixture was night with activated charcoal. The mixture was filtered stirred under nitrogen for 2 h. The reaction mixture was through CeliteR) and the filtrate was concentrated in vacuo. concentrated in vacuo and the residue was partitioned The residue was purified by column chromatography between diethyl ether (500 ml) and water (125 ml). The (Biotage, silica, 90 g), eluting with dichloromethane. The organic layer was separated, washed with aqueous Sodium appropriate fractions were combined and concentrated to give thiosulphate solution, water and brine, dried (MgSO) and Preparation 136 (3.1 g). 15 treated with charcoal. The solution was then filtered and Experimental MH" 319.0; expected 319.0 concentrated in vacuo. The residue was extracted with hexane (2x300 ml) and the combined extracts were concentrated in Preparation 107 vacuo to give the titled compound (13.8 g). Experimental MH" 228.0; expected 228.0 methyl 5-amino-3-cyano-1-2,6-dichloro-4-(trifluo romethyl)phenyl)-1H-pyrazole-4-carboxylate Preparation 111 A mixture of 5-amino-1-2,6-dichloro-4-(trifluoromethyl) N-(3-cyano-1-2,6-dichloro-4-pentafluorothiophe phenyl]-4-iodo-1H-pyrazole-3-carbonitrile (WO 98.28278 nyl-5-3-(dimethylamino)propylamino)-1H-pyra A1, 18 g. 40.3 mmol), 1,1'-bis(diphenylphosphino)fer 25 Zol-4-yl)-N-(methylsulfonyl)methanesulfonamide rocenedichloropalladium(II) (600mg) and triethylamine (10 ml), in methanol (150 ml), was placed in a pressure vessel and To a mixture of Preparation 33 (550 mg, 1.0 mmol) and heated at 60° C. under carbon monoxide (100 psi) for 60 h. triethylamine (0.33 ml, 2.3 mmol) in dichloromethane (15 The reaction mixture was filtered through Celite(R) and the ml), at 0°C., was added dropwise methanesulphonyl chloride filtrate concentrated in vacuo. To the residue was added ethyl 30 (0.19 ml, 2.3 mmol). The reaction mixture was allowed to acetate and this solution was washed with hydrochloric acid warm to room temperature and stirred for 16 h. To the reaction (0.2M) and brine. The organic phase was then separated, mixture was added water (10 ml) and the two layers were dried and concentrated in vacuo. The residue was purified by separated. The aqueous layer was extracted with dichlo flash column chromatography, eluting with ethyl acetate/hex romethane (2x20 ml) and the combined organic phases were ane (1:5). The appropriate fractions were combined and con 35 washed with brine, dried (MgSO) and concentrated in vacuo centrated and the residue re-crystallised from methanol to to give the titled compound (600 mg). give the titled compound (100 mg). Experimental MH 635.0; expected 635.0 Experimental MH379.0; expected 379.0 The invention claimed is: Preparation 108 1. A compound of formula (I) or a pharmaceutically, vet 40 erinarily or agriculturally acceptable salt thereof, Methyl 5-amino-1-2,6-dichloro-4-pentafluo rothiophenyl)-3-(trifluoromethyl)-1H-pyrazole-4- carboxylate (I) R4 45 V To a mixture of Preparation 102 (3.95 g, 13.1 mmol) and R2 N-S-R3 potassium carbonate (2.16 g. 15.6 mmol) in diethyl ether (15 ml), at 0°C., was added dropwise methyl (2Z)-3-chloro-2- cyano-4,4,4-trifluorobut-2-enoate (WO 8703781 A1, 2.79g. ( \ 13.1 mmol) in diethyl ether (6 ml). The reaction mixture was N R5 then stirred at room temperature overnight. The reaction mix 50 ture was pre-absorbed onto silica and purified by column chromatography with gradient elution, hexane:ethyl acetate 4:1 to 2:1. The appropriate fractions were combined and wherein: concentrated to give the titled compound (2.3 g). R" is phenyl optionally substituted by one or more groups H-NMR (CDC13): 3.86-3.88 (3H), 5.30-5.40 (2H), 7.86 55 independently selected from the group consisting of 7.91 (2H) halo, cyano, hydroxy, Ce alkyl, Ce haloalkyl, C. alkoxy, Ce haloalkoxy, Co alkanoyl, Ce haloal Preparation 109 kanoyl. —S(O), Calkyl. —S(O)Chaloalkyl and pentafluorothio: 2,6-dichloro-4-(trifluoromethyl)thiophenylamine 60 R’ is cyano; R is C, alkyl, Ce haloalkyl, or —(Co-alkylene)-phe To a solution of 4- (trifluoromethyl)thiophenylamine (EP nyl: 546391 A2, 4.8 g. 25.0 mmol) in acetonitrile (50 ml), at 50° C., was added N-chlorosuccinimide (6.7g, 50.0 mmol). The R" is hydrogen, C. alkyl, Chaloalkyl, -(Cosalky reaction mixture was then stirred at 50° C. for 1 h. To the 65 lene)-R7 or (Calkylene)-R; reaction mixture was added water (150 ml) and the mixture R is hydrogen; was extracted with dichloromethane (100 ml). The combined R is C, alkyl or Chaloalkyl; US 7,687,533 B2 109 110 R"is Cascycloalkyl, - S(O),R, phenyl, het, —CO.R' or N-3-cyano-1-2,6-dichloro-4-(trifluoromethyl)phenyl C(O)N(R)R’; 1H-pyrazol-4-yl)-N-(methylsulfonyl)methanesulfona R is hydroxy, C. alkoxy, C. haloalkoxy, cyano, mide; N(R)R or O C(O)R: N-3-cyano-1-2,6-dichloro-4-pentafluorothiophenyl R is C, alkyl, C- haloalkyl, C-scycloalkyl, -N(R) 1H-pyrazol-4-yl)-N-(methylsulfonyl)methanesulfona R’, phenyl or het; mide; R" and R” independently represent hydrogen, C, alkyl, N-3-cyano-1-2,6-dichloro-4-(trifluoromethyl)phenyl Chaloalkyl, Calkenyl or Ce haloalkenyl, or R 1H-pyrazol-4-yl)methanesulfonamide: additionally is —(Co-alkylene)-Cs cycloalkyl, N-3-cyano-1-2,6-dichloro-4-(trifluoromethyl)phenyl —(Co-alkylene)-phenyl or —(Co-alkylene)-het, or 10 1H-pyrazol-4-yl)-2.2.2-trifluoroethanesulfonamide: together R and R' form a 4- to 7-membered ring, N-3-cyano-1-2,6-dichloro-4-(trifluoromethyl)phenyl optionally Substituted by one or more groups indepen 1H-pyrazol-4-yl)-2.2.2-trifluoro-N-(methylsulfonyl) dently selected from the group consisting of halo, ethanesulfonamide; and hydroxy, C alkyl, Chaloalkyl, C. alkoxy and N-3-cyano-1-2.6dichloro-4-(trifluoromethyl)phenyl Chaloalkoxy; 15 n is the integer 0, 1 or 2: 1H-pyrazol-4-yl)-N-(2.2.2-trifluoroethyl)methane where het represents a four- to seven-membered heterocy Sulfonamide; clic group, which is aromatic or non-aromatic and which ora pharmaceutically, veterinarily or agriculturally accept contains one or more heteroatoms selected from the able salt thereof. group consisting of nitrogen, oxygen, Sulfur and mix 8. A pharmaceutical composition comprising a compound tures thereof, of formula (I) or a pharmaceutically, veterinarily or agricul where both phenyl and het may be optionally substituted, turally acceptable salt thereof, where the valence allows, by one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, nitro, C. alkyl, Chaloalkyl, 25 (I) C- alkenyl, Chaloalkenyl, C-galkoxy, Cha loalkoxy, Css cycloalkyl, C- alkanoyl, C- haloal kanoyl, Calkylcarbonyloxy, Calkoxycarbonyl and NR'R'; where C-scycloalkyl may be optionally substituted by one 30 or more groups independently selected from the group consisting of halo, Calkyl, Chaloalkyl, Calkenyl Chaloalkenyl, hydroxy, Calkoxy and Cha loalkoxy; and where any alkylene group may be optionally Substituted by 35 wherein: one or more halo. R" is phenyl, optionally substituted by one or more groups 2. The compound according to claim 1, wherein R' is a independently selected from the group consisting of phenyl group which bears chloro Substituents at the 2- and halo, cyano, hydroxy, C- alkyl, C- haloalkyl, C 6-positions, and a Substitutent at the 4-position selected from alkoxy, Ce haloalkoxy, Ce alkanoyl, Ce haloal the group consisting of trifluoromethyl, difluoromethoxy, tri 40 kanoyl. —S(O), Calkyl. —S(O)Chaloalkyl and fluoromethoxy, trifluoromethlythio and pentafluorothio. pentafluorothio: 3. The compound according to claim 1, wherein R is R’ is cyano; methyl, ethyl, trifluoromethyl, or 2.2.2-trifluoroethyl. R is C, alkyl, C. haloalkyl, or —(Co-alkylene)-phe 4. The compound according to claim 3, wherein R is nyl: methyl. 45 R" is hydrogen, Ce alkyl, Chaloalkyl, -(Co-alky 5. The compound according to claim 1, wherein R is lene)-R or —(C-alkylene)-R, hydrogen, Ce alkyl, Ce haloalkyl, -(Co-alkylene)-Cls R is hydrogen; cycloalkyl, cyanomethyl 2-hydroxyethyl, —(Calkylene)- het, —(Co-alkylene)-phenyl, -(Co-alkylene)-S(O).R. R is C, alkyl or Chaloalkyl; —(C-alkylene)-O C(O)R,-(C-alkylene)-C(O)N(R) 50 R’ is Cls cycloalkyl, S(O),R, phenyl, het, —COR or R or COR. C(O)N(R)R’; 6. The compound according to claim 5, wherein R is R is hydroxy, C, alkoxy, Ce haloalkoxy, cyano, hydrogen, methyl, ethyl, trifluoromethyl, 2.2-difluoroethytl. N(R)R or O C(O)R: 2.2.2-trifluoroethyl, methylsulfonyl, trifluoromethylsulfo R is C. alkyl, C- haloalkyl, Cascycloalkyl, -N (R) nyl, 2.2.2-trifluoroethylsulfonyl, aminosulfonyl, N,N-dim 55 R’, phenyl or het; ethylaminosulfonyl, methylsulfonymethyl, cyclopropyl. R" and R' independently represent hydrogen, C. alkyl, cyclobutyl, cyclopropylmethyl, 1-(trifluoromethyl)cyclopro C. haloalkyl, Calkenyl or Chaloalkenyl or R pylmethyl, cyanomethyl, methoxycarbonyl, triazolylethyl, additionally is —(Co-alkylene)-Cs cycloalkyl, pyrimidin-4-ylmethyl, 1,2,4-oxadiazol-3-ylmethyl, pyrazol —(Co-alkylene)-phenyl or —(Co-alkylene)-het, or 3-ylmethyl, 1-methyl-1H-imidazol-2-yl, 5-methyl-isoax 60 together R and R' form a 4- to 7-membered ring, aZol-3-ylmethyl 2-pyridin-4-ylethyl, aminocarbonylmethyl, optionally Substituted by one or more groups indepen benzyl or 4-fluorobenzyl. dently selected from the group consisting of halo, 7. The compound of claim 1 selected from the group con hydroxy, Ce alkyl, Chaloalkyl, Ce alkoxy and sisting of: Chaloalkoxy; N-3-cyano-1-(2,6-dichloro-4-(trifluoromethyl)phenyl 65 n is the integer 0, 1 or 2: 1H-pyrazol-4-yl)-1,1,1-trifluoro-N-methylmethane where het represents a four- to seven-membered heterocy Sulfonamide; clic group, which is aromatic or non-aromatic and which US 7,687,533 B2 111 112 contains one or more heteroatoms selected from the where C-scycloalkyl may be optionally substituted by one group consisting of nitrogen, oxygen, Sulfur and mix or more groups independently selected from the group tures thereof; consisting of halo, Calkyl, Chaloalkyl, C. alk where both phenyl and het may be optionally substituted, enyl, Chaloalkenyl, hydroxy, Calkoxy and Cha where the valence allows, by one or more substituents 5 loalkoxy; and independently selected from the group consisting of halo, hydroxy, cyano, nitro, C alkyl, Chaloalkyl, where any alkylene group may be optionally substituted by C- alkenyl, Chaloalkenyl, C-galkoxy, Cha one or more halo. loalkoxy, C.s cycloalkyl, Ce alkanoyl, Chaloal kanoyl, Calkylcarbonyloxy, Calkoxycarbonyl and 10 NR'R'; UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 7,687,533 B2 Page 1 of 1 APPLICATIONNO. : 1075931.33 DATED : March 30, 2010 INVENTOR(S) : Critcher et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

On the Title Page: The first or Sole Notice should read -- Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 620 days.

Signed and Sealed this Ninth Day of November, 2010

David J. Kappos Director of the United States Patent and Trademark Office